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Inside the Quest for a COVID-19 Vaccine

Overview

When SARS-CoV-2—the respiratory virus that causes COVID-19—first emerged, most people did not anticipate that it would result in a global public health disaster. COVID-19 rapidly spread from person to person across all borders, bringing hospitals to the brink of collapse, causing a devastating loss of life, and shutting down global economies. Scientific researchers, biotechnology companies, and government agencies quickly mobilized to develop vaccines—which prevent disease in inoculated individuals and, in some cases, also block a pathogen’s transmission from person to person—against SARS-CoV-2. The unprecedented speed of SARS-CoV-2 vaccine development reflects decades of previous research on similar coronaviruses and faster manufacturing techniques. Just over a year into the pandemic, there are already candidate vaccines for SARS-CoV-2, several of which are being rolled out worldwide. Many other vaccine candidates are currently being investigated and will hopefully become part of the toolkit in the fight against COVID-19.

On February 2-3, 2021, the New York Academy of Sciences hosted a historic symposium that brought together top virologists and vaccinologists, public health officials, and industry leaders. They reflected on the factors that contributed to the record-breaking speed of COVID-19 vaccine development, gave updates on vaccine candidates, reviewed strategies to stay ahead of future outbreaks, and discussed the many unanswered questions and challenges that lie ahead.

Symposium Highlights:

  • Decades of previous research in virology and vaccinology sped up COVID-19 vaccine development. Productive public-private coordination was also critical. >
  • Various vaccines using a range of technology platforms are currently being developed. >
  • Several COVID-19 vaccines have proven to be safe and immunogenic in Phase 1 and 2 clinical trials. Some of them have met safety and efficacy standards in Phase 3 trials and are already in the market in several countries. >
  • The emergence of new variants of SARS-CoV-2 is a source of concern for vaccine experts, but they remain optimistic. More data is still needed, but the vaccines that are already being rolled out or close to it seem to confer some degree of protection against the known variants. >
  • Many questions remain unclear, such as the duration of the protective effects of vaccines or the effects of COVID-19 vaccines in children. >
  • Investing in research and prevention strategies to bridge the pandemic preparedness gap is essential in the effort to stay ahead of future outbreaks. >

Keynote Speakers

Anthony S. Fauci, MD
National Institute of Allergy and Infectious Diseases (NIAID), NIH

Moncef Slaoui, PhD
Operation Warp Speed

Speakers

Sara Gilbert, PhD
University of Oxford

Gregory Glenn, MD
Novavax

Kathrin Jansen, PhD
Pfizer

Kevin Olival, PhD
EcoHealth Alliance

Stanley Plotkin, MD
University of Pennsylvania

Melanie Saville, MD
CEPI

Hanneke Schuitemaker, PhD
Janssen Vaccines and Prevention B.V.

Xuefeng Yu, PhD
CanSino Biologics

Tal Zaks, MD, PhD
Moderna

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Keynote Address – Slaoui

Speakers

Moncef Slaoui
Operation Warp Speed

Operation Warp Speed (OWS) and the Quest for a COVID-19 Vaccine

The Operation Warp Speed (OWS) program, initiated by the federal government, was designed to accelerate the development and distribution of COVID-19 vaccines. Moncef Slaoui, former chief scientific officer of OWS offered a broad overview of the program, the status of candidate vaccines, and key lessons from the vaccine development process.

He declared the success of the ambitious mission, which allowed for the delivery of tens of millions of vaccines in the US by February 2021. “It is remarkable that we are at that level twelve months and a few days after the virus was described,” said Slaoui. He credited this success in part to the collaborative efforts of researchers around the world, as well as the cooperation between the various government agencies and private sector partners. “This level of coordination under one leadership was unprecedented,” remarked Slaoui.

The program’s “portfolio approach,” which supported simultaneous research for 6-8 candidate vaccines, was also critical to its effectiveness. This allowed for a high level of attrition and increased capacity of manufacturing doses. Under Slaoui’s leadership, OWS also maximized speed by enabling the development, clinical trial, and manufacturing processes to proceed in parallel. Typically, manufacturing plans are not decided until after conducting the clinical trials. This strategy proved to be worth the risk when the first Phase 3 trial results from the mRNA vaccines revealed an efficacy of 95%. Likewise, OWS facilitated rapid clinical testing with little lag time between the different trial stages, and it helped private companies develop the needed manufacturing capabilities.

Slaoui, who emphasized the need for better pandemic preparedness, pointed to the spread of misinformation on vaccines and public mistrust as an “extremely disappointing dimension” that can be blamed on the politicization of the pandemic. Although the veteran vaccinologist noted OWS’s inability to effectively manage the public’s expectations and anticipate problems with distribution and delivery of the vaccine at the state level, he believes the development of multiple candidate vaccines is a monumental success.

Further Readings

Slaoui

Slaoui M, Hepburn M.

Developing Safe and Effective Covid Vaccines – Operation Warp Speed’s Strategy and Approach

N Engl J Med. 29 Oct 2020;393(18):1701-1703.

Slaoui M, Greene SE, Woodcock J.

Bridging the Gap at Warp Speed – Delivering Options for Preventing and Treating Covid-19

N Engl J Med. vol. 383,20 (2020): 1899-1901.

Keynote Address – Fauci

Speakers

Anthony S. Fauci, MD
National Institute of Allergy and Infectious Diseases (NIAID), NIH

This Year in Review: A Vaccinologist’s Perspective

Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases (NIAID), explained how it was possible to develop COVID-19 vaccines in months, when the time to develop other vaccines “had historically been measured in years.” The groundwork laid by decades of vaccine research deserves much of the credit. He traced the COVID-19 vaccine origin to 1996, when a conversation about HIV vaccine research he had with President Clinton led to the start of the NIAID Vaccine Research Center. The center—whose mission eventually grew to include other pathogens—started as an interdisciplinary effort for scientists to collaborate on research and clinical trials for an HIV vaccine.

Fauci discussed research by his colleague Peter Kwong, a structural biologist who, in 2014, mapped the envelope protein that could serve as a suitable target for a HIV-1 structure-based vaccine design. Kwong’s techniques were adapted for the development of a vaccine against other respiratory viruses. Thanks to his work, when SARS-CoV-2 appeared, researchers were able to quickly elucidate that a specially modified version of the coronavirus’ spike protein was the best antigen candidate for a vaccine.

Vaccine technologies that are being used in the COVID-19 vaccine had already been developed for other vaccines, allowing for ultrarapid COVID-19 vaccine development.

Additional platforms—including mRNA, recombinant proteins, genetically engineered viral vectors— currently used for COVID-19 vaccines were previously investigated and developed for other vaccines at the NIAID Vaccine Research Center. This scientific foundation, combined with the coordination of resources and agencies and a “harmonization of goals,” allowed for rapid vaccine development. To speed up clinical trials, “the extraordinary investments that were made decades ago in putting together the HIV clinical trial network were immediately adapted,” said Fauci.

Although Fauci recognizes the challenges of distribution, he remains optimistic. “The hope is that, when we get to the end of the spring and into the summer,” said Fauci, “we can have the overwhelming majority of people vaccinated.” He estimated that “75-80% need to be vaccinated and/or protected by previous infection” for herd immunity to be achieved. He also expressed concerns about the significant proportion of Americans that are hesitant about getting the vaccine.  “We need to respect that, but we need to try and convince them of the importance, for their own safety and the safety of their family and the American public, to get vaccinated,” he added. Fauci is confident that the techniques developed will allow for easy adaptions of the current vaccines to protect against SARS-CoV-2 mutations. The development of universal coronavirus vaccines, which is necessary to stay ahead of new coronaviruses, will hopefully be the next step.

Further Readings

Fauci

Pancera M, Zhou T, Druz A, et al.

Structure and immune recognition of trimeric pre-fusion HIV-1 Env

Nature. 2014;514(7523):455-461.

Wrapp D,  Wang N, Corbett KS, et al.

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Science. 2020;367(6483):1260-1263.

Corey L, Mascola JR, Fauci AS, Collins FS.

A strategic approach to COVID-19 vaccine R&D

Science. 29 2020 May; 368(6494):948-950.

Giurgea LT, Han A, Memoli MJ.

Universal coronavirus vaccines: the time to start is now

NPJ vaccines. 28 May 2020;5(43).

Efficacy Studies, Part One

Speakers

Gregory Glenn, MD
Novavax

Kathrin Jansen, PhD
Pfizer

Tal Zaks, MD, PhD
Moderna

Efficacy Data Updates from Moderna’s mRNA Vaccine Candidate

Tal Zaks, chief medical officer of Moderna, gave an overview of the company’s efforts to create and distribute a COVID-19 vaccine and ensure protection against new virus variants.

Zaks pointed to three factors he believes led to the creation of a vaccine in only 11 months. First, the science already existed. The mRNA platform’s central concept, which is that “you can teach a cell how to make a protein by providing it with mRNA,” was proven and shown to create neutralizing antibodies against SARS-CoV-2. Secondly, a sense of urgency due to the pandemic’s severity allowed the clinical trials to proceed quickly but, Zaks assured, “without cutting corners.” It is an unfortunate “paradox of vaccine development” Zaks explained, that the more cases occur, “the faster you will know if a vaccine works.” Finally, he credited the speed of development to Moderna’s government stakeholders. “The unsung heroes are the FDA,” he said.

Zaks then highlighted the Phase 3 clinical trial results. The trial, which was representative of minorities and included mostly frontline workers, showed 94.1% efficacy of the vaccine. He described the adverse vaccine effects as non-severe and expected. Anaphylaxis, a life-threatening allergic reaction to injectable drugs, is of concern with all vaccines. The reaction occurs at the rate of 2.5 per one million doses of the Moderna COVID-19 vaccine administered.

Zaks also discussed new Covid-19 variants. Of most concern are viruses with mutations on the receptor binding domain or the N-terminal domain, which may “improve the virus ability to escape the immune response.” Researchers saw a drop in robustness of the vaccine in the B.1.351 variant, but the vaccine remained effective. Moderna will continue to monitor mutations over time while they research booster shots to combat new variants.

Efficacy Data Updates from the Pfizer-BioNTech mRNA Vaccine Candidate

According to Kathrin Jansen, senior vice president of vaccine research and development at Pfizer, a vaccine that relies on an mRNA platform has many advantages. For example, mRNA vaccines do not use viral foreign proteins, making them safe and easy to produce at scale. Also, they generate a broad immune response, which is helpful because our knowledge of what immune responses best correlate with protection is still limited. Jansen presented data indicating that the breakthrough Pfizer-BioNTech mRNA vaccine is extremely safe and 95% effective, but she also highlighted the many challenges that lie ahead.

For instance, while the clinical trials conducted in Germany and the US captured a diverse sample from a range of ages and ethnicities, critical segments of the population were excluded due to age or clinical conditions. Clinical trials with children 12-15 are currently underway, but trials with younger children will have to wait. Pfizer-BioNTech’s vaccine needs to be kept between -80°C and -60°C, complicating storage and distribution. Jansen noted they are “making progress in a vaccine formulation that won’t require such cold temperatures.”

Data from a pseudovirus neutralization assay suggesting that sera from participants treated with the Pfizer-BioNTech vaccine can efficiently neutralize SARS-CoV-2 lineage B.1.1.7 (the variant first detected in the UK).

Highly transmissible variants that have emerged in the United Kingdom and South Africa pose what is perhaps the biggest challenge. These variants include mutations in the spike protein that Pfizer-BioNTech’s vaccine uses as a target. One of the approaches they use to research efficacy against the new variants involves creating synthetic viruses that express the mutations of interest. Then, they examine the neutralizing potential of blood sera extracted from vaccinated participants. Jansen said that data from these studies suggests that “this vaccine will continue to perform well against at least the variants that have appeared here.” However, she cautioned that this data “needs backing up by vaccine efficacy surveillance as well as animal models.”

Further Readings

Jansen

Walsh EE, Frenck RW Jr, Falsey AR, et al.

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

N Engl J Med. 17 Dec 2020;383(25):2439-2450.

Polack FP, Thomas SJ, Kitchin N, et al.

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

N Engl J Med. 31 Dec 2020;383(27):2603-2615.

Xie, Xuping et al.

Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera

bioRxiv. 7 Jan. 2021, Preprint.

Efficacy Data Updates from Novavax’s Protein-based Vaccine Candidate

Gregory Glenn gave an update on the progress of Novavax’s protein-based COVID-19 vaccine, which was not available to the public at the time of his presentation. Novavax’s recombinant nanoparticle technology produces a full-length prefusion spike protein. The protein is combined with a saponin-based Matrix-M™ adjuvant and encoded with the Sars Cov-2 spike, and produced in insect cells. Similar techniques have proven successful in Novavax influenza vaccines. Importantly, the vaccine can remain stable in a refrigerator for up to three months, lowering distribution and storage costs.

Glenn, the president of research and development at Novavax, explained that in the pre-clinical package, researchers showed protection in the lower and upper airways of Rhesus Monkeys and produced an antibody response in a trial with 131 clinically ill convalescent subjects. At the time of the presentation, Novavax was conducting its Phase 3 US/Mexico trial and did not have results. However, Glenn was able to report the results of trials in the UK and South Africa. In the UK, researchers found that the vaccine was effective at 94% for the ancestral Covid-19 strain, but decreased to 86% for the UK strain. In South Africa, where the new strain became dominant during the trial, the efficacy decreased but remained around 60%.

Based on these results, Novavax has started developing vaccines for the new variants. Glenn predicts that booster and bivalent vaccines “may become part of the annual influenza immunization regime.” The vaccines are even more important and urgent, Glenn argued, because their South African data showed that “herd immunity from previous infection is not working to protect against the new variant strain.” Glenn expressed optimism about their ability to scale up production, saying that “over the past year, we went from nothing to having eight manufacturing sites in seven countries.”

Further Readings

Glenn

Bangaru S, Ozorowski G, Turner HL, et al.

Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate

Science. 27 Nov 2020;370(6520): 1089-1094.

Keech C,  Albert G, Cho I, et al.

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine

N Engl J Med. 2020;383(24):2320-2332.

Efficacy Studies, Part Two

Speakers

Sara Gilbert, PhD
University of Oxford

Hanneke Schuitemaker, PhD
Janssen Vaccines and Prevention B.V.

Xuefeng Yu, PhD
CanSino Biologics

Update on ChAdOx1 nCoV-19/AZD1222

The Oxford-AstraZeneca adenovirus vaccine has an important advantage that distinguishes it from other vaccines currently on the market: it can be stored in a regular refrigerator for up to six months. Sarah Gilbert, professor at the University of Oxford and head of the team that developed the vaccine, emphasized the vaccine’s affordability, explaining that her team envisioned it as “a vaccine for the world.” The Oxford-AstraZeneca vaccine is being tested in clinical trials in many countries. “It was important to us to get the information on how the vaccine behaves in different populations across the world,” she said.

An early report indicated that the two-dose Oxford-AstraZeneca vaccine was about 70% efficacious at preventing COVID-19. Closer examination of the data, however, led Gilbert and her team to realize that the timing of the second dose was critical: efficacy was only 50%-60% when doses were administered less than two months apart, but waiting three months boosted efficacy levels up to 82.4%. Waiting three months to give the second dose is now the policy in the UK, the first country to grant emergency authorization for the vaccine. Gilbert and her team also found that the first dose alone is highly efficacious (76%) at protecting against COVID-19, but only for the first three months. This is enough time to reduce the risk of people contracting the disease while they wait for the booster dose.

The interval between the first dose and the booster dose of the Oxford-AstraZeneca vaccine critically determines its efficacy.

Gilbert also suggested the Oxford-AstraZeneca vaccine may be able to help curb the transmission of the virus. During clinical trials in the UK, nasal swabs of all participants were collected weekly. The scientists found 67% fewer positive samples in the vaccinated group compared to the placebo group, and that this included asymptomatic cases. The Oxford-AstraZeneca vaccine has obtained emergency approval in 23 countries so far, and the plan is to manufacture 3 billion doses by the end of 2021.

Further Readings

Efficacy Data Updates from CanSino Biologics’ Viral-Vector Vaccine Candidate

Xuefeng Yu, chairman of CanSino Biologics, provided an overview of their COVID-19 vaccine and described the China-based company’s efficacy and safety research. The CanSino Biologics’ Ad5-nCov vaccine is built on an adenovirus-based viral vector platform, a mechanism similar to the one used in the Oxford-AstraZeneca and Johnson & Johnson vaccines. Yu announced that, pending final analysis of its Phase 3 clinical trial, the company plans to file for emergency authorization in several countries soon.

The Ad5-nCov vaccine was approved for limited use by the Chinese military in June 2020. Phase 1 and 2 clinical trials conducted in Wuhan indicated the vaccine is safe and induced significant immune responses after a single dose. Over 150,000 members of the Chinese military have received a dose of the vaccine. “We haven’t had any severe adverse events in that population,” said Yu before explaining that efficacy is difficult to assess in China because “there are really no cases right now.”

CanSino Biologic’s Phase 3 clinical trial for the vaccine has been taking place in five countries since September, with Pakistan and Mexico providing the majority of the 40,000 participants. Yu explained the clinical trial results are not available to the company, which is still blinded to the treatment groups. However, recent data analyses by an independent committee has declared the vaccine meets primary safety and efficacy criteria.

The Phase 3 clinical trial for the Ad5-nCov vaccine differs from others in two critical ways. First, the vaccine’s long-term efficacy will be tested by tracking a subset of participants for one year. They are also testing a two-dose trial that includes children as young as six years old, but that data is not yet available.

Further Readings

Janssen’s Effort in the Development of an Ad26 Based COVID-19 Vaccine

The COVID-19 vaccine developed by Janssen, a pharmaceutical division of Johnson & Johnson, has just been authorized for emergency use in the US. Hanneke Shuitemaker, head of Viral Vaccine Discovery at Janssen Vaccines & Prevention B.V., explained that their Ad26.COV2.S vaccine relies on a proprietary adenovirus technology that the European Commission first approved in July 2020, in the context of an Ebola vaccine.

Phase 1 and 2a clinical trials recruited adults of all ages, including 375 participants over 65 years old. These trials revealed that the Ad26.COV2.S vaccine is safe, and most side effects were mild or moderate. The participants who were more likely to experience adverse events were younger participants and those who received the higher dose of the vaccine. Notably, both dose levels demonstrated similar immunogenicity in all age groups. Hence, Shuitemaker and her team decided to test the lower dose of their Ad26.COV2.S vaccine in Phase 3 clinical trials.

Last September, Janssen launched a Phase 3 clinical trial called ENSEMBLE, which tested the efficacy of a single dose regimen across the US, South Africa, and Latin American countries. The ENSEMBLE trial revealed that a single-dose of the Ad26.COV2.S vaccine had a 66% overall efficacy at preventing moderate to severe COVID-19. The vaccine was highly efficacious against severe disease (85%), and it provided 100% protection against COVID-19-related hospitalization and death. In the South African trial, where 97% of the infections from which SARS-CoV-2 sequence data was available, involved the new B.1.351 variant, the vaccine showed the same efficacy levels against severe disease and hospitalizations.

Although Janssen’s vaccine is not quite as efficacious against moderate COVID-19 as other vaccines already on the market, it is highly efficacious against severe COVID-19, hospitalization, and death. In addition, the one-dose vaccine does not need to be stored in ultracold temperatures and confers protection against new variants. “Overall, we are very happy with this outcome,” Shuitemaker said. “At the beginning of this journey, we had established that a single-dose vaccine with 70% efficacy would be a tremendous tool in the fight against this pandemic,” she added. A second Phase 3 clinical trial (ENSEMBLE 2), which tests the efficacy of a two-dose vaccine regimen, is currently underway.

Further Readings

Schuitemaker

Mercado NB, Zahn R, Wegmann F, et al.

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques

Nature. 2020; 586(7830):583-588.

Sadoff J, Le Gars M, Shukarev G, et al.

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine

N Engl J Med. 13 Jan2021 NEJMoa2034201.

Outbreak Predictions and Future Considerations

Speakers

Kevin Olival, PhD
EcoHealth Alliance

Stanley Plotkin, MD
University of Pennsylvania

Melanie Saville, MD
CEPI

Challenges to Prediction and Prevention of the Next Pandemic Zoonosis

According to Kevin Olival, vice president of research at EcoHealth Alliance, the threat of emerging infectious diseases has been rising for the last 70 years. Most of these infectious diseases are viral and linked to interactions between humans and wildlife. He explained that wild animals may host a diversity of viruses and that some of these viruses have the potential to infect human cells, inducing what is known as zoonotic diseases. Identifying the viruses that are more likely to jump from other species to humans and interrupting interactions between humans and the animals that carry those viruses is a challenging yet promising strategy to prevent future pandemics. In fact, two years before the COVID-19 pandemic emerged, Olival and his team published a study warning about villagers in the Yunnan province (China) being highly exposed to bats that carried SARS-related coronaviruses.

Not surprisingly, predicting where a novel infectious disease will emerge is very difficult. For instance, cataloguing all the viruses that can potentially infect each animal species involves intensive fieldwork. “Often people make the analogy with weather prediction, which was very coarse 50 years ago and we couldn’t see hurricanes coming weeks in advance,” Olival said of this nascent and complex science.

Given the multi-disciplinary and global nature of this kind of research, a centralized data platform to allow researchers to share and combine their findings will be critical. “These disparate data sets need to be put together,” said Olival.

Finally, he advocated for the need to shift policy towards pandemic prevention. It’s critical to get “policymakers to realize that there are other ways to deal with emerging infectious diseases than waiting for them to emerge and then responding,” said Olival. Once a high-risk hotspot has been identified, low-tech behavioral interventions to prevent human-animal contact may be all that is need to prevent a potentially devastating global pandemic.

Further Readings

Olival

Wang N, Li S-Y, Yang X-L, et al.

Serological Evidence of Bat SARS-Related Coronavirus Infection in Humans, China

Virologica Sinica. 2018 Feb;33(1):104-107.

Allen T, Murray KA, Zambrana-Torrelio C, et al.

Global hotspots and correlates of emerging zoonotic diseases

Nature communications. 24 Oct 2017;8(1):1124.

Latinne A, Hu B, Olival KJ, et al.

Origin and cross-species transmission of bat coronaviruses in China

Nature communications. 25 Aug 2020;11(1):4235.

United Nations Environment Programme and International Livestock Research Institute.

Preventing the Next Pandemic: Zoonotic diseases and how to break the chain of transmission

6 Jul 2020.

Lessons Learned from COVID-19 Vaccine Development for Future Pandemic Preparedness

Melanie Saville, director of vaccine research and development at the Coalition for Epidemic Preparedness Innovations (CEPI), outlined the organization’s journey through COVID-19 vaccine development and lessons learned. Created in 2017 in response to the Ebola outbreak in West Africa, CEPI seeks to “accelerate vaccines for emerging infectious diseases and ensure equitable access to the vaccines,” said Saville. Prior to COVID-19, CEPI focused mainly on MERS and rapid response platforms like mRNA. This put CEPI on good footing when they shifted focus to COVID-19 at the start of January 2020.

By April of 2020, CEPI had raised over $1.5 billion in funding and entered partnerships with nine entities using varied strategies to develop COVID-19 vaccines. “Speed, scale and access,” the career virologist said, were the main criteria in determining investments. For speed, they carefully chose their partners and made early investments to ensure manufacturing capabilities to meet their accessibility goals of 2 billion vaccine doses worldwide by the end of 2021. That they invested in a portfolio of vaccines meant that if a vaccine failed, facilities could then be used for another vaccine. This manufacturing investment also helped with scalability, which is a problem particularly for smaller companies that have to resolve supply chain issues with sufficient materials and facilities.

CEPI joined the ACT Accelerator, established by the World Health Organization, to speed-up development of vaccines, diagnostics, and therapeutics and launched their taskforce, “Agility,” to better track variants. Saville sees these coalitions and organizations as a model and foundation for future pandemic responses. Overall, she’s optimistic. The pandemic has created a global desire for countries to invest and work together. “We have seen a revolution in vaccinology,” said Saville.

The Coalition for Epidemic Preparedness Innovations (CEPI) adopted a portfolio approach to vaccine development, supporting the development of many different vaccine types summarized in this slide.

Further Readings

Saville

Lurie N,  Saville M, Hatchett R, Halton J.

Developing Covid-19 Vaccines at Pandemic Speed

N Engl J Med. 2020;382(21): 1969-1973.

Thanh Le T, Andreadakis Z, Kumar A, et al.

The COVID-19 vaccine development landscape

Nat Rev Drug Discov. 2020 May;19(5): 305-306.

The Plague Year of 2020 and Its Effect on Vaccinology

In the final talk of the symposium, vaccinologist Stanley Plotkin reflected on how SARS-CoV-2 has impacted vaccinology. He praised the “all hands on deck” approach that we witnessed in 2020, with experts around the world getting involved and collaborating to develop multiple highly effective vaccines. Plotkin was also optimistic about the effect that the pandemic has had on vaccine acceptance. “Now, most people in all countries are pleading for vaccines, and to me that is a positive thing,” he said.

He also highlighted the importance of virology and other basic sciences. He explained that a handful of coronavirus researchers did the work that became the cornerstone of COVID-19 vaccines. According to Plotkin, “we need to support all those basic sciences, so that when we need something practical, we have the information we need to start working on a solution.”

Plotkin also listed a series of unknowns that researchers will need to figure out going forward. For example, the issue of mucosal responses to the vaccine. SARS-CoV-2 is a mucosal pathogen that takes hold in the nasal pharynx before spreading to the lungs and other organs. It is still unclear to what extent the current vaccines prevent mucosal replication. “Understanding how well they [prevent mucosal replication] has terribly important epidemiological implications regarding herd immunity and the spread of the disease,” he said.

Due to the tendency of SARS-CoV-2 to mutate, Plotkin said we have to face the possibility of a yearly vaccination. He advocated for the creation of regional labs that can monitor and quickly report on mutations across the world, something that is done with influenza. He also emphasized that we need to learn more about veterinary viruses, as they “have caused problems, are causing problems, and will cause problems.”

Further Readings

Plotkin

WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation, et al.

Placebo-Controlled Trials of Covid-19 Vaccines – Why We Still Need Them

N Engl J Med. 2021 Jan 14;384(2):e2.

Plotkin SA.

Vaccination Against Severe Acute Respiratory Syndrome Coronavirus 2

J Pediatric Infect Dis Soc. 10 Nov 2020;9(5): 517-518.

Plotkin SA, Halsey N.

Accelerate COVID-19 Vaccine Rollout by Delaying the Second Dose of mRNA Vaccines

Clin Infect Dis. 27 Jan 2021;ciab068.

Plotkin S.

History of vaccination

Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12283-7. Epub 2014 Aug 18.

The Effects of Screen Time on the Developing Brain

Overview

Screens were ubiquitous before, but during the COVID-19 pandemic they became a lifeline for everyone’s professional and personal lives. Children spend more time on electronic devices than ever before—with virtual school, video streaming, social media, and multiplayer games. Many parents are concerned about the impact excessive screen time might have on the developing brain. In this e-Briefing experts discuss the pros and cons of screen time as well as its effects on the developing brain, and give practical tips for parents navigating the digital world with their children during the COVID-19 pandemic.

In this eBriefing, You’ll Learn:

  • The content of digital media matters; parents should differentiate between types of screen time.
  • Shared engagement with digital media is important.
  • There are resources available to help parents navigate the digital world.
  • “Real-world” parenting strategies can and should be extended into the digital world.

Speakers

Sonia Livingstone, DPhil
London School of Economics and Political Science

Michael Preston, PhD
Sesame Workshop

Jenny Radesky, MD
Department of Pediatrics, University of Michigan Medical School

Michael Robb, PhD
Common Sense Media

COVID-19: Screen Time and the Developing Brain

Sonia Livingstone, DPhil

London School of Economics and Political Science

Dr. Livingstone is a Professor of Social Psychology in the Department of Media and Communications at the London School of Economics and Political Science. She received her DPhil in Psychology from the University of Oxford. She has published 20 books on media, especially children’s rights, risks, and opportunities in the digital world and media literacy, including “The Class: Living and Learning in the Digital Age” (New York University Press, with Julian Sefton-Green) and most recently “Parenting for a Digital Future: How hopes and fears about technology shape children’s lives” (Oxford University Press, with Alicia Blum-Ross). Recipient of many honors, she has advised the UK and European government and the United Nations on children’s internet safety and rights in the digital environment. Dr. Livingstone currently directs the Digital Futures Commission (with the 5Rights Foundation) and the Global Kids Online project (with UNICEF). She is Deputy Director of the UKRI-funded Nurture Network and leads work packages for two European H2020-funded projects: ySKILLS (Youth Skills) and CO:RE (Children Online: Research and Evidence). Founder of the EC-funded 33 country EU Kids Online research network, she is a #SaferInternet4EU Ambassador for the European Commission.

Michael Preston, PhD

Joan Ganz Cooney Center at Sesame Workshop

Michael Preston is the Executive Director of the Joan Ganz Cooney Center at Sesame Workshop, a research and innovation lab that focuses on the challenges of educating children in a rapidly changing media landscape. The Cooney Center conducts original research on emerging education technologies and collaborates across sectors to put this research into action. Prior to joining Sesame Workshop, Michael’s work focused on using technology to improve teaching and learning, drive student agency and interest, and create models for systemic change in K-12 and university contexts. He is a co-founder of CSforALL, the hub for the national Computer Science for All movement. He designed and led digital learning initiatives at the NYC Department of Education and at Columbia University’s Center for Teaching and Learning. He earned a PhD in Cognitive Science in Education from Teachers College, Columbia University and a BA in East Asian Studies from Harvard University.

Jenny Radesky, MD

University of Michigan

Dr. Radesky is a Developmental Behavioral Pediatrician and Assistant Professor of Pediatrics at the University of Michigan Medical School. She received her M.D. from Harvard Medical School, trained at Seattle Children’s Hospital and Boston Medical Center, and her clinical work focuses on developmental and behavioral conditions in low-income and underserved populations. Her NIH-funded research focuses on the use of mobile/interactive technology by parents and young children and how this relates to child self-regulation and parent-child interaction. She was the lead author of the American Academy of Pediatrics (AAP) policy statements Media and Young Minds in 2016 and Digital Advertising to Children in 2020.

Michael Robb, PhD

Common Sense Media

Michael Robb is senior director of research at Common Sense, overseeing the research program, evaluation of organization impact, and program development research. Dr. Robb has been involved in issues involving media and children for over 20 years. He has published research on the impact of electronic media on young children’s language development, early literacy outcomes, and problem-solving abilities in a variety of academic journals. He also has supervised community educational outreach efforts, helping parents and teachers make the most of quality children’s programming. His work has been featured in the New York Times, Washington Post, Wall Street Journal, Huffington Post, and many other news outlets. Dr. Robb received his B.A. from Tufts University and M.A. and Ph.D. in psychology from UC Riverside

Further Readings

Livingstone

Livingstone S, Blum-Ross A.

Parenting for a digital future: how parents’ hopes and fears about technology shape children’s lives

2020 July 1; New York: Oxford University Press

United Nations Children’s Fund (UNICEF)

The state of the World’s Children 2017: Children in a Digital World

2017 Dec

Livingstone S

Digital by default: the new normal of family life under COVID-19

Parenting for a Digital Future: A Blog about growing up in a digital world. 2020 May 13.

Preston

Sesame Street Resources to Support Children and Parents during COVID-19

Caring for Each Other

Preston M

Re-evaluating what matters during a time of crisis

Joan Ganz Cooney Center Blog. 2020 April 1.

Radesky

Radesky J, Christakis D, Hill et al.

Media and Young Minds

Pediatrics. 2016 Nov 1; 138(5).

Radesky J, Chassiakos YR, Ameenuddin N, Navsaria D.

Digital Advertising to Children

Pediatrics. 2020 July 1; 146(1).

Robb

Robb M

Screen Time in the Age of the Coronavirus

Common Sense Media Blog. 2020 April 7.

Common Sense Media Recommendation for Educational Apps

https://www.commonsensemedia.org/app-lists

Common Sense Media Quarterly Survey Series

How Teens Are Coping and Connecting in the Time of the Coronavirus

2020 April 8

What Physics Tells Us About the World

Speaker

Jim Al-Khalili, PhD
University of Surrey

Overview

With his newly released book The World According to Physics as a point of reference, Jim Al-Khalili offers an illuminating look at what physics reveals about the world. Shining a light on the most profound insights revealed by modern physics, he invites us to reflect on what this crucially important science can tell us about the universe and the nature of reality itself. Educational and enlightening, this talk illustrates why physics is indispensable to understanding the world around us and invites us all to share in the profound adventure of seeking truth.

In This eBriefing, You’ll Learn:

  • How the three pillars of modern physics ― quantum theory, relativity, and thermodynamics ― must come together if we are ever to have a full understanding of reality
  • Relatable examples and thought-provoking analogies that elucidate the speculative frontiers of the field, and the physics that underpin our everyday experiences and technologies

Jim Al-Khalili, PhD

University of Surrey

Jim Al-Khalili is a British theoretical physicist, author and broadcaster. He is Professor of Theoretical Physics at the University of Surrey, a regular broadcaster and presenter of science programs on BBC radio and television, and the author of numerous books, including The World According to Physics, Quantum: A Guide for the Perplexed; and Life on the Edge: The Coming of Age of Quantum Biology.

He received his PhD in theoretical nuclear physics in 1989 and has published over a hundred research papers on quantum physics. He is a recipient of the Royal Michael Faraday medal and the Institute of Physics Kelvin Medal. In 2016 he received the inaugural Stephen Hawking Medal for Science Communication. He is a fellow of the Royal Society and lives in Southsea, England.

Resources

Al-Khalili

Al-Khalili, Jim

The World According to Physics

Princeton University Press, 2020

Al-Khalili, Jim

Quantum: A Guide for the Perplexed

Orion Publishing Co., 2012

Al-Khalili, Jim

Quantum Mechanics (A Ladybird Expert Book)

Penguin Books, 2017

Einstein, Albert

Relativity: The Special and General Theory

Methuen & Co Ltd, 1920

Al-Khalili, Jim

The Life Scientific

BBC Radio 4, 2020

Innovative Vaccines: Tackling Infectious Diseases and Emerging Threats

Overview

While the development of vaccines against infectious diseases has had a profound impact on life expectancy, there remain many resistant and emerging infections for which no effective vaccines are available, such as malaria, HIV, and Zika. Recent advances in biotechnology and our understanding of human immunity hold great promise for conquering new diseases. For example, advances in structural biology allow for the discovery of new antigens that can target broad viral families, such as influenza, or complex parasites like malaria. Novel clinical trials for maternal immunizations have shown encouraging results for reducing dangerous diseases in newborn infants. Furthermore, recent progress in DNA- or RNA-based vaccines holds promise for inexpensive and fast production, which is especially favorable for responding to emerging epidemics. Learn more about recent breakthroughs in vaccine development in this summary of our May 20, 2019 symposium, which gathered the world’s leaders in vaccine development.

Symposium Highlights:

  • Emerging infectious diseases can be treated quickly with a passive vaccine containing human monoclonal antibodies isolated from the blood of an infected patient.
  • Targeting multiple stages of the malaria life cycle is a promising strategy for the development of a successful vaccine targeting this complex parasite.
  • Clinical trials show promise for maternal immunizations in protecting newborn infants from respiratory syncytial virus (RSV) and Group B streptococcus.
  • A vaccine containing the influenza hemagglutinin (HA) fusion protein without the head domain can elicit protection against a broad group of influenza viruses.
  • Synthetic DNA and mRNA vaccines are simple to manufacture and show promise for treating a wide range of diseases, including Ebola, HIV, Zika, influenza, and malaria.
  • A promising new adjuvant, AS01, has contributed to breakthrough vaccines for Malaria, tuberculosis, and shingles.

Speakers

James E. Crowe, Jr., MD
Vanderbilt University Medical Center

Greg Glenn, MD
Novavax

Adrian Hill, PhD
University of Oxford

Kathrin Jansen, PhD
Pfizer

Wayne Koff, PhD
Human Vaccines Project

Sallie Permar, MD, PhD
Duke University

Rino Rappuoli, PhD
GlaxoSmithKline

David Weiner, PhD
The Wistar Institute

Drew Weissman, MD, PhD
University of Pennsylvania

Ian Wilson, DPhil
The Scripps Research Institute

Event Sponsors

Silver

Bronze

Academy Friend

Serendipity Foundation

New Approaches for Understanding the Immune System for Vaccine Development

Speaker

James E. Crowe, Jr.
Vanderbilt University Medical Center

Human Antibodies and Repertoires for Emerging Infectious Diseases

James Crowe, of Vanderbilt University Medical Center, discussed his lab’s work developing treatments for emerging infectious diseases using monoclonal human antibodies. “Antibodies essentially are a passive vaccine,” explained Crowe. Currently, it takes about two years to develop a vaccine for an infectious disease agent, which is not quick enough for outbreak response. Therefore, Crowe argues that antibodies are the “most appropriate public health measure for most emerging infections.” Crowe’s group is working on two strategies for developing human antibody drugs: one focuses on speed, whereas the other aims to develop broad antibodies ahead of an outbreak.

The Rapid Rational Antibody Design and Delivery (RRADD) project uses ultra-fast techniques to respond to a specific outbreak in the moment. They recently used Zika as a test case. Starting with a blood sample from a surviving patient, their facility used single-cell RNA-sequencing to produce a list of antibody genes within a day. These antibodies were quickly produced and then tested in a high-throughput real-time cell culture system to assay for protection against Zika infection. Leading candidates were tested in mouse and primate models, leading to the discovery of protective antibodies within 78 days.

Illustrations of antibody (Ab)- antigen (Ag) complexes for human monoclonal antibodies (mABs) recently discovered in the AHEAD100 project.

The second strategy is the Advanced Human Epidemic Antibody Defenses (AHEAD100) project, a methodical approach that aims to develop antibodies for the 100 most likely infectious diseases ahead of any future outbreaks. Interestingly, they found broad antibodies that work across viruses of a related class, such as noroviruses, alphaviruses, and flu.

Further Readings

Crowe

Bangaru S, Lang S, Schotsaert M, et al.

A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface.

Cell. 2019;177(5):1136-1152 e1118.

Finn JA, Crowe JE, Jr.

Impact of new sequencing technologies on studies of the human B cell repertoire.

Curr Opin Immunol. 2013;25(5):613-618.

Flyak AI, Ilinykh PA, Murin CD, et al.

Mechanism of human antibody-mediated neutralization of Marburg virus.

Cell. 2015;160(5):893-903.

Hasan SS, Miller A, Sapparapu G, et al.

A human antibody against Zika virus crosslinks the E protein to prevent infection.

Nat Commun. 2017;8:14722.

Sapparapu G, Fernandez E, Kose N, et al.

Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice.

Nature. 2016;540(7633):443-447.

Wang H, Shi Y, Song J, et al.

Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.

Cell. 2016;164(1-2):258-268.

Taking on the Big Challenges Facing Novel Vaccine Development

Adrian Hill
University of Oxford

Wayne Koff
Human Vaccines Project

New Generation Malaria Vaccines

Adrian Hill from the University of Oxford presented his work on the development of a malaria vaccine. Malaria causes 500,000 deaths each year, but developing an effective vaccine is challenging. “Even if you get a good antigen, you need remarkably high immunogenicity,” Hill explained. Therefore, Hill’s group aims to develop a vaccine that targets multiple stages of the malaria parasite life cycle.

In the first stage, mosquitos introduce malaria sporozoites into a human host. Hill’s group and others have been developing vaccines that combine malaria antigens with virus-like particles to induce antibody production against sporozoites. Hill and colleagues are developing R21, a more potent version of the RTS,S vaccine currently in Phase III trials. In R21, 100% of the molecules encode the sporozoite antigen. Studies show that this formulation allows for a lower dose, as antibody titers are indistinguishable between a 10 µg dose of R21 and a 50 µg dose of RTS,S. Furthermore, R21 shows a more durable response, with higher titers at six months versus RTS,S. By 2020, they expect efficacy results from the first Phase IIB trial.

As the malaria life cycle progresses, sporozoites infect liver cells, where the parasite matures. “[To target] the liver stage, you need T-cells” said Hill. Inducing T-cells requires a viral vector approach. Research on mice and clinical studies from Hill’s group show that the ME-TRAP antigen viral vector can induce high levels of resident memory T-cells in the liver. There are ongoing field clinical trials for this vaccine.

The Future of Vaccine Development

Wayne Koff, the president and CEO of the Human Vaccines Project, described the nonprofit’s research decoding the human immune system. Vaccines for complex infectious and non-communicable diseases such as HIV, tuberculosis, and cancer have been difficult to develop. Koff believes that a better understanding of human immunity is essential for accelerating vaccine development for these diseases.

One strategy is to investigate why some people respond to vaccines and infections much better than others. “If we can understand this, we can get at the pathogens we haven’t been able to tackle,” said Koff. Recent developments in single cell multi-omics allow for an in-depth analysis of an individual’s immune system. A growing body of evidence suggests that immunity biomarkers at baseline can predict an individual’s response to immunization. Researchers performed single cell RNA-sequencing on innate immune cells before immunization and successfully identified biomarkers predictive of the response to the Hepatitis B vaccine. By integrating all of the pre-immunization data, investigators could build biostatistical models that accurately predicted final antibody titers, while revealing pathways that may be involved in the response mechanism.

This data suggests that “we all have an immune set point,” said Koff, which leads to the opportunity to modulate this set point before immunization to improve outcomes. Furthermore, smaller trials that account for individual variability and assay predictive signatures may be more effective than standard large vaccine efficacy trials.

Further Readings

Hill

Gola A, Silman D, Walters AA, et al.

Prime and target immunization protects against liver-stage malaria in mice.

Sci Transl Med. 2018;10(460).

Greenwood B, Doumbo OK.

Implementation of the malaria candidate vaccine RTS,S/AS01.

Lancet. 2016;387(10016):318-319.

Klein SL, Shann F, Moss WJ, Benn CS, Aaby P.

RTS,S Malaria Vaccine and Increased Mortality in Girls.

MBio. 2016;7(2):e00514-00516.

Koff

Antia A, Ahmed H, Handel A, et al.

Heterogeneity and longevity of antibody memory to viruses and vaccines.

PLoS Biol. 2018;16(8):e2006601.

Briney B, Inderbitzin A, Joyce C, Burton DR.

Commonality despite exceptional diversity in the baseline human antibody repertoire.

Nature. 2019;566(7744):393-397.

Liu X, Speranza E, Munoz-Fontela C, et al.

Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus.

Genome Biol. 2017;18(1):4.

Soto C, Bombardi RG, Branchizio A, et al.

High frequency of shared clonotypes in human B cell receptor repertoires.

Nature. 2019;566(7744):398-402.

Tsang JS, Schwartzberg PL, Kotliarov Y, et al.

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

Cell. 2014;157(2):499-513.

Vaccines to Protect Newborns: The Next Frontier

Speakers

Greg Glenn
Novavax

Kathrin Jansen
Pfizer

Sallie Permar
Duke University

Advances in Maternal Immunization

Kathrin Jansen from Pfizer discussed recent advances in maternal immunization. Infants under six months are the most vulnerable to infection, but most vaccines are not available at this early stage of life. Furthermore, “20% of stillbirths seem to be associated with an infectious disease,” said Jansen. Active antibody transfer from mother to baby during pregnancy is an essential mechanism for protecting infants from infectious diseases. The goal of maternal immunization is to enhance maternal antibody levels to further protect newborns. Jansen explained that these vaccines could either “augment pre-existing antibody responses or induce a de novo response” to infections the mother has not yet been exposed to.

Schematic depicting maternal immunization strategy.

Jansen presented recent findings for maternal vaccines targeting respiratory syncytial virus (RSV) and Group B streptococcus bacteria, two infections that are especially deadly for newborn infants. In a recent Phase I/II trial, the Group B streptococcus vaccine induced high levels of antibody titers for up to six months in healthy adults, giving confidence to move forward for testing in pregnancy. Recent structural biology studies of RSV identified a metastable form of the viral fusion protein. With this form in mind, a screen for vaccine candidates revealed molecules that were 30 times more powerful than the current licensed prophylactic antibody in rodents. Data from a Phase I/II study will be available later this year.

Protecting Infants from RSV via Maternal Immunization

Greg Glenn, of Novavax, presented recent progress on the development of an RSV maternal vaccine. RSV is the leading cause of hospitalization of infants in the United States. While the Pfizer version of the vaccine, described by Kathrin Jansen, resembles the metastable prefusion form of the viral fusion protein, the Novavax version targets an earlier, stable form known as the prefusogenic form. This vaccine contains a near full-length fusion protein, but with deletions in a furin cleavage site. “These deletions fix the protein structure, and that allows it to be very stable,” Glenn explained. Through stabilizing the prefusogenic form, the virus is prevented from successfully infecting cells, which allows the vaccine to be produced in culture with higher yields. Furthermore, all antibodies that target the metastable prefusion form also target the prefusogenic form. Immunization with the Novavax vaccine induces antibodies to a variety of viral epitopes, which are also transferred to the infant.

Schematic showing the different forms of the fusion (F) protein of the RSV virus.

Currently, Novavax is running a worldwide Phase III randomized placebo-controlled trial to evaluate protection of infants against RSV with their maternal vaccine. The vaccine was given “to immunized mothers in third trimester, and we monitored infants intensely for six months,” explained Glenn. The trial showed a 40% reduction in their primary endpoint, which was medically significant RSV lower respiratory tract infection at 90 days old.

Next Generation Vaccines to Eliminate Congenital Cytomegalovirus: We are halfway there

Sallie Permar, of Duke University, shared her work developing an effective vaccine for congenital cytomegalovirus (CMV), which is the most common congenital infection and cause of birth defects worldwide. Developing a vaccine has been tricky, as it’s unknown exactly what maternal immune responses are protective against congenital CMV transmission. Permar’s group is investigating these questions with a novel, non-human primate model as well as data analysis from previous vaccine trials.

Permar and colleagues infected seronegative rhesus monkeys with CMV at the beginning of pregnancy. “We used a model of severe pathology with maternal CD4+ T-cell depletion followed by an intravenous inoculation to ask whether antibodies alone could be protective against congenital CMV transmission,” explained Permar. Data from a small group of animals suggests that treatment with passive antibodies from donor plasma prior to inoculation prevents fetal transmission. This result indicates that stimulating potent antibody responses could be a promising route to an effective maternal CMV vaccine.

Previous trials of a vaccine containing glycoprotein B, the main fusion protein of the virus, have shown partial effectiveness. Permar’s group probed the trial data to investigate what immune responses correlate with protection against CMV in infected versus uninfected vaccine recipients. “The ability of vaccine-elicited antibodies to bind to glycoprotein B-transfected cells was higher in uninfected vaccinees,” said Permar, suggesting that eliciting antibodies that bind to glycoproteins is a promising vaccine target. Furthermore, the infected group of vaccine recipients was still protected against specific CMV strains, suggesting that a broader immunogen might be more effective.

Further Readings

Permar

Baraniak I, Kropff B, Ambrose L, et al.

Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies.

Proc Natl Acad Sci U S A. 2018;115(24):6273-6278.

Nelson CS, Huffman T, Jenks JA, et al.

HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions.

Proc Natl Acad Sci U S A. 2018;115(24):6267-6272.

Pass RF, Zhang C, Evans A, et al.

Vaccine prevention of maternal cytomegalovirus infection.

N Engl J Med. 2009;360(12):1191-1199.

Renzette N, Gibson L, Bhattacharjee B, et al.

Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection.

PLoS Genet. 2013;9(9):e1003735.

New Technologies for Vaccine Development

Speakers

Rino Rappuoli, PhD
GlaxoSmithKline

David Weiner, PhD
The Wistar Institute

Drew Weissman, MD, PhD
University of Pennsylvania

Ian Wilson, DPhil
The Scripps Research Institute

Guiding Vaccine Candidates: Antibodies That Can Neutralize Influenza and Malaria

Ian Wilson, from the Scripps Research Institute, shared his recent work investigating the structural biology of antibodies to guide vaccine candidates for influenza and malaria. Wilson’s group aims to “design immunogens or even small molecules from the structural information about how antibodies bind.”

Human antibodies that neutralize a broad range of flu subtypes have been characterized in the last ten years. Interestingly, the broadest antibodies bind to the less immunogenic “stem” domain of the influenza hemagglutinin (HA) fusion protein, rather than the “head” domain. “We are using this information to try to think of novel vaccines,” said Wilson. “If we chop off the immunogenic head, then we can target the response against the stem.” Indeed, a recently developed headless HA construct elicited protection against all influenza A group 1 antibodies in mice and monkeys.

Wilson’s group has also probed the structural biology of human antibodies elicited in recent RTS,S malaria vaccine trials. Cryo-EM revealed the structure of antibodies binding to the circumsporozoite protein (CSP) of malaria: the antibodies spiral all the way around the NANP peptide repeats of the protein. Furthermore, antibodies in the spiral bind in close proximity, and often, somatic mutations strengthen these homotypic contacts for a more stable spiral. Future work will explore the relevance of this spiral structure for vaccine purposes.

Synthetic DNA Approaches for Difficult Infectious Disease Targets

David Weiner, of the Wistar Institute, presented recent findings on the development and efficacy of synthetic DNA vaccines. DNA vaccines are “very consistent, very simple to manufacture, temperature stable,” and allow for local transfection without systemic expression, explained Weiner. Recent early stage clinical trials have shown promising results for using synthetic DNA vaccines as immunotherapy to treat human papillomavirus (HPV)-related cancers. Synthetic DNA is also promising for treating emerging infectious diseases. Wiener discussed three examples, Ebola, MERS, and Zika, where prophylactic treatment with synthetic DNA induced a 95%–100% response rate, and transmission into the clinic occurred in only 7–15 months.

Weiner also discussed his group’s work developing a DNA-encoded monoclonal antibody (dMAb) platform. Muscle or skin tissue “is transfected and becomes a factory for expression of the protein. The idea is getting [the antibody] secreted into the bloodstream at detectable levels,” said Weiner. They have developed dMAbs targeting Ebola, HIV, and Zika that induce robust antibody expression and viral protection in animal models. For HIV, multiple dMAbs can be delivered at one time, which has been shown to induce broad neutralizing titers against nine HIV subtypes in non-human primates.

Weiner and collaborators are also working to engineer DNA cassettes that encode self-assembling nanoparticles directly in vivo. Nanoparticles targeting HIV showed improved immune responses versus the monomeric form: “It’s dose sparing, it’s much faster seroconversion and much higher titers, and it elicits very good CD8+ T-Cells,” Weiner said.

mRNA Vaccines: A New Era in Vaccinology

Drew Weissman, of the University of Pennsylvania, discussed recent advances in the development of mRNA vaccines for infectious diseases. Why use RNA? In theory, the cost of mRNA production would be much less than that of protein, which requires large-scale cell culture followed by purification that differs for every protein. Weissman’s group developed a platform using nucleoside-modification and purification techniques to optimize mRNA structures that induce high and long-lived translation when delivered within lipid nanoparticles to peripheral sites.

Mice vaccinated with the A/Cal/7/2009 HA mRNA vaccine challenged with the distant flu virus H5N1 showed full protection. These results suggest immunization with HA mRNA could result in a universal flu vaccine.

Weissman discussed mRNA vaccines developed with their platform targeting influenza, HSV-2, HIV, and malaria, which have all shown promising results in animal models. For influenza, a single immunization with an mRNA vaccine coding for the hemagglutinin (HA) fusion protein in mice resulted in titers 50 times higher than the current FDA approved vaccine. As a mechanism of action, they found that the lipid nanoparticles used for vaccine delivery induce T- follicular helper cells, which drive long-term immune memory and are “critical in the induction of potent antibody responses,” explained Weissman. Furthermore, their mRNA vaccines induce responses to subdominant epitopes in the presence of dominant epitopes, which isn’t seen with whole proteins. This response is useful because subdominant epitopes, such as the HA stem domain, can be broadly cross-reactive across viral subtypes. Vaccinated mice challenged with distant flu viruses were fully protected, “suggesting that using a full HA could give you a universal vaccine,” said Weissman.

Transforming New Technologies into Vaccines: Genomics, Adjuvants and Self-Amplifying RNAs

Rino Rappuoli, of GlaxoSmithKline, shared how new technologies will allow us to conquer new diseases. Recent advances have allowed for major improvements in reverse vaccinology — using human genomics and structural biology to discover new antigens and instruct vaccine design. “Today we have the tools of synthetic biology,” said Rappuoli. At GSK, “we are using self-amplifying mRNA instead of simple mRNA. We use the replicon of the alphavirus to amplify the RNA and give a better response.” Nucleic acid vaccines work well in animal models, and the challenge now is testing whether it will work well in humans.

Rappuoli also discussed encouraging new advances in antigen delivery using nanoparticles or Generalized Modules for Membrane Antigens (GMMA).  While self-assembling natural nanoparticles have been around for years, fully synthetic nanoparticles have only recently been designed. “We are going from mimicking nature to completely computationally designing vaccines,” explained Rappuoli. GMMAs consist of outer membrane vesicles from bacteria, which are engineered to release these vesicles in large quantities with the desired antigens. Rappuoli also highlighted recent developments in adjuvants, substances within vaccines that enhance the immune response to antigens. A promising new adjuvant, AS01, has contributed to breakthrough vaccines for Malaria, tuberculosis, and shingles. Moving forward, Rappuoli aims to use these new technologies to target vaccines for the elderly, emerging infections, and antimicrobial resistance.

Further Readings

Wilson

Impagliazzo A, Milder F, Kuipers H, et al.

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen.

Science. 2015;349(6254):1301-1306.

Laursen NS, Friesen RHE, Zhu X, et al.

Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin.

Science. 2018;362(6414):598-602.

Lee PS, Wilson IA.

Structural characterization of viral epitopes recognized by broadly cross-reactive antibodies.

Curr Top Microbiol Immunol. 2015;386:323-341.

Oyen D, Torres JL, Cottrell CA, Richter King C, Wilson IA, Ward AB.

Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts.

Sci Adv. 2018;4(10):eaau8529.

Oyen D, Torres JL, Wille-Reece U, et al.

Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein.

Proc Natl Acad Sci U S A. 2017;114(48):E10438-E10445.

Steel J, Lowen AC, Wang TT, et al.

Influenza virus vaccine based on the conserved hemagglutinin stalk domain.

MBio. 2010;1(1).

Rappuoli

Garcon N, Chomez P, Van Mechelen M.

GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives.

Expert Rev Vaccines. 2007;6(5):723-739.

Lal H, Cunningham AL, Godeaux O, et al.

Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults.

N Engl J Med. 2015;372(22):2087-2096.

Rappuoli R, Aderem A.

A 2020 vision for vaccines against HIV, tuberculosis and malaria.

Nature. 2011;473(7348):463-469.

Rappuoli R, Mandl CW, Black S, De Gregorio E.

Vaccines for the twenty-first century society.

Nat Rev Immunol. 2011;11(12):865-872.

Climate Science: Decision-Making in a Warmer World

Overview

Climate change is a growing threat with global impact. Shifts in the climate present special challenges for urban areas where more than half of the world’s population lives. New York City residents, for example, are already feeling the effects through recurrent flooding in coastal communities, warmer temperatures across all five boroughs, and strains in the city’s infrastructure during heavy downpours and extreme weather events. As a result, cities like New York require the best-available climate science to develop tangible policies for resilience, mitigation, and adaptation.

On March 15, 2019, climate scientists, city planners, and community and industry stakeholders attended the Science for Decision-Making in a Warmer World summit at the New York Academy of Sciences to discuss how cities are responding to the effects of climate change. The event marked the 10th anniversary of a successful partnership between the New York City Panel on Climate Change (NPCC), the City of New York, and the New York Academy of Sciences. Established in 2008, the NPCC has opened new frontiers of urban climate science to build the foundation for resiliency actions in the New York metropolitan region.

Learn about the NPCC’s latest research findings and their implications for New York City and other cities seeking to identify and mitigate the effects of climate change in this summary.

Meeting Highlights

  • NPCC research provides tools to inform and shape climate change resilience in New York City and other cities around the globe. 
  • Shifts in mean and extreme climate conditions significantly impact cities and communities worldwide. 
  • Cities can move forward by adopting flexible adaptation pathways, an overall approach to developing effective climate change adaptation strategies for a region under conditions of increasing risk.
  • There is a growing recognition that resilience strategies need to be inclusive of community perspectives.

Speakers

Dan Bader
Columbia University, New York City Panel on Climate Change

Jainey Bavishi
New York City Mayor’s Office of Recovery and Resiliency

Sam Carter
Rockefeller Foundation

Alan Cohn
New York City Department of Environmental Protection

Kerry Constabile
Executive Office of the UN Secretary General

Susanne DesRoches
New York City Mayor’s Office of Recovery and Resiliency

Alexander Durst
The Durst Organization

Sheila Foster
Georgetown, New York City Panel on Climate Change

Vivien Gornitz
Columbia University, New York City Panel on Climate Change

Mandy Ikert
C40 Cities Climate Leadership Group

Klaus Jacob
Columbia University, New York City Panel on Climate Change

Michael Marrella
New York City Department of City Planning

Richard Moss
American Meteorological Society

Kathy Robb
Sive, Paget, and Riesel

Seth Schultz
Urban Breakthroughs

Daniel Zarrilli, PE
New York City Office of the Mayor

Climate Change, Science, and New York City

Speakers

Alan Cohn
New York City Department of Environmental Protection

Susanne DesRoches
New York City Mayor’s Office of Recovery and Resiliency

Alexander Durst
The Durst Organization

Michael Marrella
New York City Department of City Planning

Daniel Zarrilli (keynote)
New York City Office of the Mayor

James Gennaro (panel moderator)
New York State Department of Environmental Conservation

Keynote: Preparing for Climate Change — NPCC and Its Role in New York City

Daniel Zarrilli, of the New York City Office of the Mayor, gave the first keynote presentation. In addition to outlining NPCC history, he emphasized the meaning of NPCC to the city. NPCC has provided the tools to inform policy since before Hurricane Sandy in 2012. Because of NPCC, Zarrilli stated, people now know that the waters around New York City are rising “twice as quickly as the global average” and that climate change will affect communities disproportionately. The city can and will take on the responsibility to protect those who are most vulnerable.  Zarrilli highlighted steps the Mayor’s Office is taking: fossil fuel divestment, bringing a lawsuit against big oil for causing climate change, and launching a new OneNYC strategic plan to confront our climate crisis, achieve equity, and strengthen our democracy. He concluded by saying that with “8.6 million New Yorkers and all major cities watching,” NPCC is providing the best possible climate science to drive New York City policy.

Panel 1: NPCC and Its Role in New York City

How are NPCC findings used in developing resiliency in New York City?

The first panel was moderated by William Solecki of Hunter College Institute for Sustainable Cities – City University of New York, and featured three city representatives, Susanne DesRoches, of the New York City Mayor’s Office of Recovery and Resiliency; Michael Marrella, of the New York City Department of City Planning; Alan Cohn, of the New York City Department of Environmental Protection; and one industry stakeholder, Alexander Durst, of the Durst Organization.

DesRoches noted that the NPCC research has made possible a proliferation of guidelines regulating building design in the city. In fact, the New York City Climate Resiliency Design Guidelines, released the same day that the panel took place, provide instruction on how to use climate projections in the design of city buildings. The Department of City Planning also uses NPCC data in its Coastal Zone Management Program to require that coastal site developers to disclose and address current and future flood risks. Marrella added that NPCC research tools allow public and private stakeholders to make informed decisions on how to shape policy. NPCC methods and approaches are also being used climate data is also being used for New York State and national projections.

Panelists also addressed how New York City’s mitigation goals enable resilience in the face of climate change challenges. DesRoches pointed to the city’s aggressive climate targets, including an “80% [emissions] reduction by 2050,” and a goal to limit temperature increase to 1.5°C, as targeted by the Paris Agreement (UN Climate Change 2015). She gave two examples of adaptations that align with the City’s mitigation goals: adapting high “passive house” and green building standards for a reduced carbon footprint; and diversifying how the city receives energy, including the development of a renewable energy grid. Cohn added that the Department of Environmental Protection aims to free up capacity in water conservation and implement the use of methane as an energy source. With resilience in mind, Durst stressed that energy models should be uniform and based on the future, not just today.

Further Readings

Zarrilli

Wallace-Wells D.

The Uninhabitable Earth: Life after Warming

New York: Tim Duggan Books; 2019

Panel 1

UN Climate Change. The Paris Agreement.

What is the Paris Agreement?

Dec (2015)

NYC Mayor’s Office of Recovery and Resiliency.

Climate Resiliency Design Guidelines.

March (2019)

Wuebbles DJ, Fahey DW, Hibbard KA, Dokken DJ, et al.

Climate Science Special Report: Fourth National Climate Assessment

U.S. Global Change Research Program, Washington, DC, USA, 2017;1-477.

Rosenzweig C, Solecki W, DeGaetano A, O’Grady M, et al.

Responding to climate change in New York State: The ClimAID integrated assessment for effective climate change adaptation in New York State

Final report, NYSERDA. 2011;1-149

Findings from the New York City Panel on Climate Change

Panelists

Dan Bader
Columbia University, New York City Panel on Climate Change

Sheila Foster
Georgetown, New York City Panel on Climate Change

Vivien Gornitz
Columbia University, New York City Panel on Climate Change

Klaus Jacob
Columbia University, New York City Panel on Climate Change

Julie Pullen (panel moderator)
Jupiter Intelligence

Panel 2: Latest Findings from the New York City Panel on Climate Change

What types of information are the most useful?

The second panel was moderated by Julie Pullen of Jupiter Intelligence, and featured four NPCC members who presented the latest NPCC3 report findings: Vivien Gornitz, Klaus Jacob, and Daniel Bader of Columbia University; and Sheila Foster, of Georgetown Law.

The latest NPCC3 findings confirmed climate projections from the 2015 report as the projections of record for New York City planning and decision-making. For example, by the end of the century, “ocean levels will be higher than they are now due to thermal expansion; changes in ocean heights; loss of ice from Greenland and Antarctic Ice Sheets; land-water storage; vertical land movements; and gravitational, rotational, and elastic ‘fingerprints’ of ice loss,” said Gornitz. Under the NPCC’s new Antarctic Rapid Ice melt (ARIM) scenario, there could be up to a 9.5 ft. increase in sea level rise by 2100 at the high end of the projections. The new report advises that levies or raised streets might reduce the effects that sea level rise will have on New York City’s coastline.

Vulnerability to climate change varies by neighborhood and socioeconomic status. Foster presented a new three-dimensional approach to community-based adaptation through the lens of equity: distributional, contextual, and procedural. Distributional equity emphasizes disparities across social groups, neighborhoods, and communities in vulnerability, adaptive capacity, and the outcomes of adaptation actions. Contextual equity emphasizes social, economic, and political factors and processes that contribute to uneven vulnerability and shape adaptive capacity. Procedural equity emphasizes the extent and robustness of public and community participation in adaptation planning and decision-making.

Echoing Mayor Bloomberg’s sentiment that “if you can’t measure it, you can’t manage it,” Jacob presented the proposed NPCC New York City Climate Change Resilience Indicators and Monitoring system (NYCLIM). Through the new proposed NYCLIM system, NPCC recommends climate, impact, vulnerability, and resilience indicators for the City’s decision-making processes.

Further Readings

Cities as Solutions for Climate Change and Closing Remarks

Keynote Speaker and Panelists

Jainey Bavishi
New York City Mayor’s Office of Recovery and Resiliency

Sam Carter
Rockefeller Foundation

Kerry Constabile
Executive Office of the UN Secretary General

Seth Schultz
Urban Breakthroughs

Mandy Ikert (keynote)
C40 Cities Climate Leadership Group

Richard Moss (panel moderator)
American Meteorological Society

Keynote: Role of Cities in Achieving Progress

Mandy Ikert, of C40 Cities Climate Leadership Group, gave the second keynote presentationThe Future We Don’t Want, a study recently released by C40, the Urban Climate Change Research Network (UCCRN), and Acclimatise found that billions of urban citizens are at risk of climate-related heat waves, droughts, floods, food shortages, and blackouts by 2050 (UCCRN 2018). Cities are situated at the forefront of these effects and urgently need to respond. Ikert stated that “we live in an urbanizing world,” where 68% of the world’s population will be living in cities by 2050, up from approximately 54% today.” Ikert stressed that “mayors and city agencies are directly accountable to their constituency” in order to protect and preserve their lives and livelihood. She also urged cities to reach out to researchers to obtain accurate modeling for extreme events. Cities have the potential to account for 40% of the emissions reductions required to align with the Paris Agreement’s goal to limit temperature rise to 1.5°C (UN Climate Change 2015). Therefore, the way a city responds to climate change, Ikert said, determines how livable and competitive it will be in the future.

Panel 3: City Stakeholders and Beyond

How can knowledge networks and city networks improve interactions to achieve climate change solutions?

The final panel was moderated by Richard Moss of the American Meteorological Society, and featured Corinne LeTourneau, of the North America Region, 100 Resilient Cities; Kerry Constabile, of the Executive Office of the UN Secretary General; Jainey Bavishi, of the New York City Mayor’s Office of Recovery and Resiliency; and Seth Schultz, of Urban Breakthroughs, spoke about the enormous value and knowledge of stakeholders.

In this session, all of the participants highlighted that many cities are playing a critical role in meeting the challenge of climate change, both through efforts to reduce their own greenhouse gas footprints, and to update infrastructure and programs to meet the needs of their citizens as climate change impacts occur.

Panelists discussed how finances are a major challenge to addressing climate change. For example, Constabile noted that a small percentage of megacities in developing countries have credit ratings. This lack of “creditworthiness” hinders cities from raising their own bonds and attracting private investment, both of which are significant sources of funding for climate-related projects. Schultz suggested that private money may jumpstart some climate resiliency and adaptation efforts, and stated that eight of ten of the world’s largest countries are funding research on climate change. LeTourneau and Schultz identified that without the climate data to assess risks, money will not be directed to the areas of greatest need. LeTourneau highlighted the importance of describing how climate change affects risks and “the bottom line” in a way that decision makers and citizens find compelling and relatable.

Panelists also highlighted that climate does not have boundaries, but government bodies do. As Bavishi pointed out, New York City is lucky that climate change adaptation has been codified into law. Chief resilience officers are retained even after city funding is spent, so continuity is in place. City governments around the country and the globe are following suit, but as the panelists pointed out, these ideas should spread more widely.

Closing Remarks

NPCC member Michael Oppenheimer remarked that the NPCC offers a “local picture at granular level with the best possible science.” Hurricane Sandy taught the City about its vulnerability and drove research on flood tides and rising coastal tides. With the 2010 NPCC report, he said, a firm research agenda was drafted that shifted the City’s view of climate change to resiliency. Oppenheimer stressed that NPCC science is useful for policy and praised New York City for utilizing NPCC data in policy decisions. In closing, Oppenheimer said that dissemination assures that communities worldwide are able to use NPCC data.

Further Readings

Ikert

Rosenzweig C, Solecki W, Romero-Lankao P, Mehrtotra S, et al.

Climate change and cities: Second assessment report of the urban climate change research network

Cambridge: Cambridge University Press Eds; 2018

United Nations, Department of Economic and Social Affairs

World Urbanization Prospects: The 2018 Revision, Online Edition

Population Division (2018)

Moss RH, Avery S, Baja K, Burkett M, et al.

Evaluating Knowledge to Support Climate Action: A Framework for Sustained Assessment

Wea., Clim., Soc. 2019 Apr 4(2019)

The New York City Mayor’s Proclamation

Whereas: Global issues are often felt most deeply at the local level, and in the face of worldwide threats to our environment, infrastructure, and economy, cities have the power and responsibility to lead our planet in the right direction.  After Hurricane Sandy, when the devastating effects of climate change hit home for far too many of our residents, New York City reaffirmed our commitment to building a sustainable path forward.  On the 10th anniversary of its founding, it is a great pleasure to recognize the New York City Panel on Climate Change for its exceptional leadership in this work.

Whereas: Since 2008, the NPCC’s innovations in urban climate science have propelled New York to the forefront of the global fight against climate change.  Its recommendations have informed ambitious policies that have helped the five boroughs recover from past damage and emerge stronger, and its successful partnership with the City of New York and the New York Academy of Sciences demonstrates the power of collaboration between the public sector, industry and local leaders, and the scientific community.  With the NPCC’s guidance, we are better prepared to anticipate and conquer the climate challenges that lie ahead.

Whereas: New Yorkers have always been known for their resiliency and boldness, and our city must meet concerns of this scale with solutions that our worthy of its residents.  From increasing our coastal resiliency to pioneering a global protocol for cities to attain carbon neutrality by 2050, my administration remains steadfast in our efforts to protect people of all backgrounds from the impacts of climate change.  As we continue to grapple with the grave risks that global warming poses, we are grateful to the NPCC for providing our city with the rigorous science needed to thrive in our rapidly changing world.  Today’s Summit offers a wonderful opportunity to applaud this organization for a decade of service to New York City, and I look forward to the progress its members will continue to inspire in the years ahead.

Now therefore, I, Bill De Blasio, Mayor of the City of New York, do hereby proclaim Friday, March 15th, 2019 in the City of New York as:

 “NEW YORK CITY PANEL ON CLIMATE CHANGE DAY”

Proclamation of the Mayor of New York City

Resolution of Inflammation, Infection and Tissue Regeneration

Overview

For centuries, physicians and scientists have thought of inflammation as the body’s acute response to infection or injury, but in recent decades it’s become clear that chronic inflammation drives pathologies as diverse as cancer, diabetes, and Alzheimer’s disease. Controlling this aberrant inflammation, however, has proven difficult. Conventional anti-inflammatory drugs work by antagonizing the body’s pro-inflammatory hormones, but that approach also suppresses immunity, opening the patient to secondary infections. A newer strategy relies on recently discovered resolution mediators, compounds that the body makes naturally to resolve inflammatory responses without suppressing other parts of the immune system. Drugs targeting this process have shown immense potential to treat many of the world’s most serious diseases, with fewer side effects than existing therapies.

On June 25–26, 2018, the New York Academy of Sciences hosted Resolution of Inflammation, Infection and Tissue Regeneration, a symposium featuring many of the top researchers in the rapidly developing field of resolution pharmacology. In two days of oral presentations, a poster session, and an extensive panel discussion, speakers and attendees reviewed the biggest advances and challenges in resolution biology. The meeting covered the basic biology of inflammation and its resolution, studies on animal models of chronic and acute diseases, and clinical trials of promising new inflammation-resolving drugs.

Speakers

Nan Chiang, PhD
Brigham and Women’s Hospital, Harvard Medical School

Michael Conte, MD
University of California, San Francisco

Jesmond Dalli, PhD
William Harvey Research Institute, QMUL

Gabrielle Fredman, PhD
Albany Medical Center

Catherine Godson, PhD
University College Dublin

Dipak Panigrahy, MD
Beth Israel Deaconess Medical Center, Harvard Medical Center

Paul Ridker, MD, MPH
Brigham and Women’s Hospital, Harvard Medical School

Charles Serhan, PhD, DSc
Brigham and Women’s Hospital, Harvard Medical School

Patricia Sime, MD
University of Rochester School of Medicine

Matthew Spite, PhD
Brigham and Women’s Hospital, Harvard Medical School

Ira Tabas, MD, PhD
Columbia University

Mark Tepper, PhD
Corbus Pharmaceuticals

Kevin Tracey, MD
The Feinstein Institute for Medical Research

Thomas Van Dyke, DDS, PhD
Forsyth Center for Clinical and Translational Research

Sponsors

eBriefing Support

Bronze Sponsor

Metagenics

Academy Friends

Additional Support Provided by

Resolution Mediators and Mechanisms in Inflammation: Leads for 21st Century

Speakers

Charles Serhan
Brigham and Women’s Hospital, Harvard Medical School

Charles Serhan, from the Brigham and Women’s Hospital and Harvard Medical School, opened the meeting with a keynote presentation that spanned the history of resolution physiology, a field he pioneered. Physicians and scientists have known about inflammation since antiquity, primarily as an acute condition associated with injury and infection. In recent years, however, biologists have come to understand that chronic inflammation underlies many non-communicable diseases, including cancer, diabetes, Alzheimer’s disease, and Parkinson’s disease.

Serhan has focused on how acute inflammation normally resolves, and how this process sometimes malfunctions, leading to chronic inflammation. When he entered the field, “in the textbooks, the resolution of acute inflammation was thought to be a passive event,” Serhan said. Pro-inflammatory molecules became diluted over time, bringing the inflammation to an end. Through an extensive series of cell culture, animal, and human studies, Serhan and his colleagues have overturned that model, showing that multiple families of pro-resolving molecules actively antagonize the inflammatory process and promote healing. These small fatty acid-derived molecules, now known as lipoxins, resolvins, protectins, and maresins, act through specific cellular receptors to orchestrate a complex switch from inflammation to resolution.

Several classes of chemical mediators actively drive inflammation resolution.

Serhan, like many others at the meeting, is now exploiting those findings to design new drugs that could treat a wide range of chronic conditions far more effectively than current anti-inflammatory compounds, with fewer side effects. “This is really a paradigm shift in thinking about how to treat inflammation, using agonists to stimulate resolution rather than inhibitors that eventually become immunosuppressive,” said Serhan.

Speaker Presentation

Further Readings

Serhan

Serhan, C.N., and Levy, B.D.

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators.

J. Clin. Invest. 2018;128(7):2657-2669.

Serhan, K., Gartung, A., and Panigrahy, D.

Drawing a link between the thromboxane A2 pathway and the role of platelets and tumor cells in ovarian cancer.

Prostaglandins Other Lipid Mediat. 2018;137: 40-45.

Session 1: The Fire Inside

Speakers

Dipak Panigrahy, MD
Beth Israel Deaconess Medical Center, Harvard Medical Center

Ira Tabas, MD, PhD
Columbia University

Cancer Progression: Failure to Resolve?

Dipak Panigrahy, of Beth Israel Deaconess Medical Center and Harvard Medical School, started the meeting’s first session by discussing his work on inflammation resolution in cancer. Researchers first discovered the link between inflammation and tumor growth in the late 19th  century, but only recently has it become clear that inflammation is an essential initiator of at least some types of cancer. A mouse model of pancreatic cancer, for example, does not get the disease unless it first develops pancreatitis.

Unfortunately, most current anti-inflammatory drugs suppress the immune system, allowing established tumors to become even more aggressive. To find better solutions, Panigrahy began dissecting the mechanisms linking cancer and inflammation. He discovered that cancer-killing interventions such as chemotherapy leave behind debris from the killed tumor cells. In a mouse model of ovarian cancer, that debris worsens the disease. “So the debris will stimulate the tumor growth. It’s kind of a double edged sword of cancer therapy,” said Panigrahy. Adding specialized pro-resolving mediator molecules (SPMs) stimulates phagocytic cells to engulf the cellular debris, inhibiting further tumor growth. Treatments that boost SPMs could work synergistically with chemotherapy to attack numerous types of cancer.

The Interplay between Efferocytosis and Inflammation Resolution

Ira Tabas from Columbia University continued the theme of clearing cellular debris, with a presentation about his group’s work on the process. Macrophage cells function as the body’s garbage collectors, engulfing the remains of dead cells through efferocytosis. The process is critical for healing damaged tissue and resolving inflammation, but it requires intensive metabolic management by the macrophage. “When a macrophage is eating multiple dead cells … it might be like you sitting down eating 20 filet mignons, and then half an hour later eating 20 more,” said Tabas, adding that “it’s a tremendous metabolic load.”

Efferocytosis of dead cells requires macrophages to handle a high metabolic load.

Tabas’s team studies efferocytosis in mouse models of heart disease. They found that eliminating a single gene in the animals blocks efferocytosis and leads to much worse disease, highlighting the importance of efferocytosis in resolving inflammation. Next, the researchers used an elegant in vitro assay to demonstrate that the degradation products from engulfing one dead cell regulate the macrophage’s ability to engulf a second one. The macrophages use another tightly regulated process to recycle the membranes of the dead cells. Together, the mechanisms explain how macrophages can keep their efferocytosis rates as high as possible without becoming metabolically overloaded.

Speaker Presentations

Further Readings

Panigrahy

Chang, J., Bhasin, S.S., Bielenberg, D.R., et al.

Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin.

FASEB J. 2018: fj201800019RR.

Serhan, K., Gartung, A., and Panigrahy, D.

Drawing a link between the thromboxane A2 pathway and the role of platelets and tumor cells in ovarian cancer.

Prostaglandins Other Lipid Mediat. 2018;137:40-45.

Yang, H., Wang, W., Romano, K.A., et al. (2018).

A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice.

Sci Transl Med. 2018; 10(443).

Tabas

Ghorpade, D.S., Ozcan, L., Zheng, Z., et al.

Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance.

Nature. 2018;555(7698):673–677.

Ozcan, L., Ghorpade, D.S., Zheng, Z., et al.

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance.

Cell Rep. 2016;15(10): 2214–2225.

Subramanian, M., Ozcan, L., Ghorpade, D.S., et al.

Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity.

PLoS ONE. 2015;10(8): e0135842.

Session 2a: Vessels in Distress

Speakers

Michael Conte, MD
University of California, San Francisco

Gabrielle Fredman, PhD
Albany Medical Center

Paul Ridker, MD, MPH
Brigham and Women’s Hospital, Harvard Medical School

Providing Proof of Principle for Atherosclerosis, Lung Cancer, Kidney Disease, and Osteoarthritis: Lessons from CANTOS

Paul Ridker from Brigham and Women’s Hospital began the second session with a keynote address on the CANTOS clinical trial. This trial sought to address several questions about inflammation resolution in cardiovascular disease.

Atherosclerosis is a leading cause of vascular disease worldwide. Researchers have identified numerous factors that predict the onset of atherosclerosis, including high blood pressure, cholesterol, and markers of chronic inflammation, but it remains unclear which of these factors are causative and which merely correlate with pathogenesis.

Current treatments for atherosclerosis focus on lowering blood pressure and cholesterol levels, but Ridker and his colleagues wanted to target inflammation instead. To do that, they used a human monoclonal antibody drug called canakinumab, which binds the pro-inflammatory protein interleukin-1beta. IL-1beta triggers a series of signals that promote inflammation and also increase blood levels of C-reactive protein (CRP), a biomarker of atherosclerosis. A pilot study on 1,400 patients sought to determine how much canakinumab it would take to reduce patients’ CRP levels to baseline, but the drug was so powerful that it worked at all doses tested.

The CANTOS trial enrolled over 10,000 patients to test canakinumab in patients with cardiovascular disease.

Based on those data, Ridker’s team designed a much larger trial, enrolling over 10,000 patients. The participants all had high CRP levels even after aggressive cholesterol-lowering therapy, indicating that they were still suffering from chronic inflammation. Those treated with canakinumab showed dramatic reductions in CRP, and concomitantly lower rates of cardiovascular events over the trial’s seven-year run, compared to controls who received a placebo. Crucially, treated patients showed no signs of immunosuppression, and most of the drug’s side effects were mild or even beneficial. For example, patients in the treatment groups had significantly lower rates of overall cancer mortality and chronic kidney disease than controls.

The results show that atherosclerosis treatment plans should focus on both cholesterol and inflammation. “If we’re going to beat this disease, we have to [target] both of these processes,” said Ridker.

Resolution of Vascular Injury: Mechanisms and Therapeutic Implications

Michael Conte, of the University of California, San Francisco, addressed what happens in the next step of modern vascular disease management: surgery. “It really doesn’t matter what we do when we touch blood vessels, whether we inflate a balloon, scrape out plaque, do a bypass graft or insert a catheter, we are faced with a scarring response … that has a classic inflammatory and resolution phase,” Conte explained.

In animal models of vascular injury, damaged blood vessels become inflamed, then produce specialized pro-resolving mediators (SPMs) to resolve the inflammation. Conte’s group also found that delivering extra SPMs locally to the site of injury significantly improves inflammation resolution and healing.

To put that finding into practice, the investigators have developed thin film polymers that can release SPMs directly into a vessel over time. They wrap the film around the blood vessel during surgery and leave it in place to deliver the molecules for days afterward. The system reduces graft thickness in a rabbit bypass graft model, and improves outcomes in mouse models of aneurysm surgery and thrombosis. Conte is also conducting a clinical trial testing the safety of naturally isolated SPM-stimulating compounds in humans.

Dysregulation of Resolution Pathways in Atherosclerosis

Gabrielle Fredman from Albany Medical Center continued the vascular theme, discussing her work on how dead cells get removed from atherosclerotic plaques. As a plaque develops on the wall of an artery, the cells at the center begin to die. This weakens the structure of the plaque and makes it more likely to rupture. Fredman studies this process in genetically modified mice that develop atherosclerosis when fed a high-fat diet. Treating these mice with SPMs decreases necrosis in their plaques, but how?

When cells die through apoptosis, or programmed suicide, macrophages rapidly engulf the resulting debris. Fredman and her colleagues found that cells undergoing necroptosis, such as those in the core of a plaque, are apparently much less appetizing. Macrophages fed necroptotic cells take them up much more slowly and in smaller pieces. “This resembles something like a nibbling process rather than a whole engulfment process,” said Fredman. The researchers subsequently found that a molecule called CD47 on the necroptotic cells may act as a “don’t eat me” signal, slowing their engulfment by macrophages. Adding SPMs, however, boosts macrophages’ efferocytosis responses enough to overcome that signal.

Speaker Presentations

Further Readings

Ridker
Fredman

Cai, B., Thorp, E.B., Doran, A.C., et al.

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation.

Proc. Natl. Acad. Sci. U.S.A. 2016;113(23):6526–6531.

Doran, A.C., Ozcan, L., Cai, B., et al.

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis.

J. Clin. Invest. 2017;127(11):4075–4089.

Yurdagul, A., Doran, A.C., Cai, B., et al.

Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis.

Front Cardiovasc Med. 2018;4:86.

Session 2b: Medical Mystery Tour

Speakers

Nan Chiang, PhD
Brigham and Women’s Hospital, Harvard Medical School

Jesmond Dalli, PhD
William Harvey Research Institute, QMUL

Kevin Tracey, MD
The Feinstein Institute for Medical Research

The Role of n-3 Docosapentaneoic Acid-derived Pro-resolving Mediators in Systemic Protection

Jesmond Dalli, of the William Harvey Research Institute at the Queen Mary University of London, began the second part of the session with a presentation linking circadian rhythms and vascular inflammation. Disruption in circadian rhythms has been linked to metabolic disorders and cardiovascular disease progression, so Dalli wondered whether specialized pro-resolving mediators (SPMs) also showed circadian patterns.

Dalli’s team took blood samples from seven healthy volunteers throughout a 24-hour period, and found that the level of n-3 DPA, a precursor to SPMs, rose and fell in a consistent cycle. In contrast, patients with cardiovascular disease lose this circadian regulation, and have consistently low levels of SPMs. Additional experiments in mice confirmed the link. “This suggests that [loss] in circadian regulation of this pathway leads to a breakdown [in] early morning activation of platelets and monocytes,” said Dalli, “and that this then promotes cardiovascular disease.” He and his colleagues found that the cholesterol-lowering drugs atorvastatin and pravastatin increase the production of two SPMs, reinforcing other groups’ findings that these drugs combat cardiovascular disease through multiple mechanisms.

Pro-resolving Receptors: Mechanisms and Signaling

Nan Chiang from Harvard Medical School talked about the cellular receptors that respond to SPMs. One well-characterized SPM, resolvin D2, is a potent promoter of inflammation resolution; even extremely low doses of resolvin D2 can limit peritonitis and enhance survival in animal models of sepsis.

Resolvin molecules signal through specific cellular receptors to generate their observed effects.

Chiang suspected that resolvin D2 might act through a G-protein coupled receptor, so she tested a panel of 77 of these receptors whose functions had not yet been identified. That screen revealed that the receptor GPR18 responds strongly to resolvin D2. Human macrophages overexpressing GPR18 respond more strongly to resolvin D2 than controls; and mice lacking GPR18 don’t benefit from resolvin D2 treatment during experimental E. coli infection or sepsis, confirming that GPR18 is a biologically relevant receptor for resolvin D2.

In addition to resolvins, Chiang also studies another family of SPMs, known as maresin conjugates in tissue regeneration (MCTRs). She discovered that MCTRs act through a receptor called CysLT1 to reduce vascular leakage after injury. Knowing the receptors for these SPMs should facilitate the design of drugs with similar effects.

Molecular Approaches to Bioelectronic Medicine

Kevin Tracey, from the Feinstein Institute for Medical Research, started the meeting’s second day with a keynote presentation on bioelectronic medicine. Instead of manipulating body chemistry with chemicals, bioelectronic treatments connect electronic devices to the nervous system to stimulate desired responses. “The idea of bioelectronic medicine is a mechanistic approach to using electrons to replace drugs,” Tracey explained.

The vagus nerve connects the brain to multiple organs, and also the immune system.

About thirty years ago, when Tracey was a practicing neurosurgeon, a young patient died in his arms from shock. That spurred him to search for new drugs that could block shock-causing cytokines. In one experiment, his lab injected a promising anti-inflammatory drug directly into the brains of mice with experimentally induced strokes. It blocked inflammatory cytokines in the brain, but also in other organs throughout the animals’ bodies. That made no sense, as the molecule shouldn’t have been able to escape the brain.

The researchers subsequently discovered that the vagus nerve can trigger an anti-inflammatory reflex throughout the body, connecting the nervous system directly to the immune system. Subsequent work by others revealed that the vagus nerve stimulates the production of pro-resolving mediators in multiple organs and tissues. Tracey’s team is now conducting clinical trials to treat Crohn’s disease with an implanted electronic device that stimulates the vagus nerve and triggers this response.

Speaker Presentations

Further Readings

Dalli

Arnardottir, H., Orr, S.K., Dalli, J., and Serhan, C.N.

Human milk proresolving mediators stimulate resolution of acute inflammation.

Mucosal Immunol. 2016;9(3):757–766.

Serhan, C.N., Chiang, N., Dalli, J., and Levy, B.D.

Lipid mediators in the resolution of inflammation.

Cold Spring Harb Perspect Biol. 2014;7(2):a016311.

Serhan, C.N., Chiang, N., and Dalli, J.

The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution.

Semin. Immunol. 2015;27(3):200–215.

Chiang
Tracey

Gunasekaran, M., Chatterjee, P.K., Shih, A., et al.

Immunization Elicits Antigen-Specific Antibody Sequestration in Dorsal Root Ganglia Sensory Neurons.

Front Immunol. 2018;9: 638.

Tracey, K.J. (2018).

Neurons Are the Inflammatory Problem.

Cell. 2018;173(5):1066-1068.

Zanos, T.P., Silverman, H.A., Levy, T., et al. (2018).

Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity.

Proc. Natl. Acad. Sci. U.S.A. 2018; 115(21):E4843-E4852.

Session 3: Better Living through Chemistry

Speakers

Patricia Sime, MD
University of Rochester School of Medicine

Matthew Spite, PhD
Brigham and Women’s Hospital, Harvard Medical School

Temporal Biosynthesis of Pro-Resolving Lipid Mediators by Distinct Immune Cell Subsets during Skeletal Muscle Injury and Regeneration

Matthew Spite, of Brigham and Women’s Hospital and Harvard Medical School, returned the focus to chemistry, with a discussion of the specialized pro-resolving mediators (SPMs) that orchestrate healing from injuries. Using mass spectrometry, Spite identified all of the lipids produced in an injured mouse muscle as it recovers. The lipid profile changes over time and increases in the well-known resolvin subset of SPMs correlate with healing. That correlation persists whether the muscle damage comes from a toxin or exercise. “A lot of these pathways were consistent in two distinct models of injury,” said Spite. His team next characterized the macrophages present in the healing tissue, and found a distinct shift from pro-inflammatory to pro-resolving macrophage types, in sync with the shift in the lipid profile.

COPD: Inflammation, Infection and Resolution

Patricia Sime, from the University of Rochester School of Medicine, discussed the role of SPMs in chronic obstructive pulmonary disease (COPD). COPD, a chronic inflammatory condition, is now the fourth leading cause of death worldwide. It is caused primarily by smoking. “There’s actually no drug treatment for COPD,” said Sime,  “so it’s a huge unmet need.”

Exposing mice to precisely controlled doses of cigarette smoke provides a model of human lung inflammation.

To better understand COPD, Sime used mass spectrometry to profile the lipids in exhaled breath condensates from patients with the disease as well as  healthy controls. That pointed toward the SPMs resolvin D1 and D2 as critical mediators of inflammation resolution in the lung. Treating a mouse model of chronic smoking with resolvins decreases inflammation in the animals’ lungs. Sime hopes to exploit these findings to develop new therapies for COPD, as well as prophylaxis against lung damage from all types of smoke inhalation.

Speaker Presentations

Further Readings

Spite

Hellmann, J., Sansbury, B.E., Wong, B., et al.

Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair.

J. Invest. Dermatol. 2018;(18)31728-7.

Wu, B., Werlin, E.C., Chen, M., et al.

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.

J. Vasc. Surg. 2018;(18)31349-1.

Sime

Bhat, T.A., Kalathil, S.G., Bogner, P.N., et al.

Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections.

J. Immunol. 2018;200(8):2927-2940.

Croasdell, A., Lacy, S.H., Thatcher, T.H., et al.

Resolvin D1 Dampens Pulmonary Inflammation and Promotes Clearance of Nontypeable Haemophilus influenzae.

J. Immunol. 2016;196(6):2742-2752.

Lugade, A.A., Bogner, P.N., Thatcher, T.H., et al.

Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection.

J. Immunol. 2014;192(11): 5226-5235.

Session 4: The Hunger Flames

Catherine Godson, PhD
University College Dublin

Mark Tepper, PhD
Corbus Pharmaceuticals

Thomas Van Dyke, DDS, PhD
Forsyth Center for Clinical and Translational Research

Lipoxins and Lipoxin Mimetics Attenuate Diabetic Complications

Catherine Godson of University College Dublin opened the meeting’s final session with a presentation on lipoxins in diabetes. As a result of the obesity pandemic, diabetes has become an immense global health problem. One of the most serious complications of diabetes is kidney disease. “Those with the most profound diabetic kidney disease… have almost 50% increased mortality,” said Godson, adding that “there are no effective therapeutics” for the condition.

In an effort to change that, Godson and her colleagues have examined the lipoxin A4 molecule, a specialized pro-resolving molecule (SPM) that attenuates inflammation in animal models. The researchers found that lipoxin A4 attenuates molecular signals that promote fibrosis, helps maintain epithelial tissue integrity, and reduces activation of the inflammatory cytokine TGF-beta. “All of these are important potential targets of lipoxin actions in the context of chronic kidney disease and diabetic kidney disease,” said Godson.

Lipoxins mediate multiple protective and inflammation-resolving effects.

Next, Godson investigated lipoxin A4’s effects in animal models. Mice fed a high-fat diet become obese and develop kidney and liver disease similar to that seen in obese humans. Treating the animals with lipoxin A4 protects their livers and kidneys. Godson and her colleagues have also found that lipoxin A4 can reverse atherosclerosis in the overfed mice.

To translate those findings into practical medications, Godson is now working with synthetic chemists to develop drugs that can mimic the effects of lipoxin A4 in humans.The team has developed several promising leads, and is now testing them in various preclinical models.

Targeting the Endocannabinoid-Specialized Pro-resolution Mediator Pathway with Lenabasum to Treat Chronic Inflammatory/Fibrotic Diseases

Mark Tepper from Corbus Pharmaceuticals discussed lenabasum, the company’s synthetic, oral, small-molecule, selective cannabinoid receptor type 2 (CB2) drug. The endocannabinoid system activates the resolution of inflammation through the CB2 receptor. This GPCR is commonly found on activated immune cells during inflammation.

Based on promising preclinical results, Corbus tested lenabasum in the human clinical study (“blister model”) that has been designed to follow the progression of an inflammatory stimulus and subsequent resolution of inflammation. This study showed that lenabasum indeed stimulates inflammation resolution, reduces pro-inflammatory mediators, and promotes the clearance of bacterial endotoxins.

Corbus is now conducting more advanced clinical trials in patients with various chronic inflammatory conditions, including scleroderma, dermatomyositis, cystic fibrosis, and lupus. So far, the safety profile has been favorable with no serious adverse events attributed to lenabasum and no evidence of immunosuppression.

The Role of Resolution Phase Mediators in Oral Medicine

Thomas Van Dyke, from the Forsyth Center for Clinical and Translational Research, gave the final presentation: a look inside the mouth. Over 90% of American adults over age 30 suffer from gingivitis, and about 14% of them – or 22 million people – have severe periodontal disease. Conventional anti-inflammatory drugs can slow the progression of this disease, but can’t stop it.

A resolvin-containing mouthwash treats periodontal disease in an animal model.

In a rabbit model of periodontitis, Van Dyke has found that rinsing the animals’ mouths with a SPM analog called benzo-lipoxin A4 reverses periodontitis and restores lost bone in the jaw. That’s far better than any previously studied treatment. “There is no [prior] example of pharmacologically induced bone regeneration in periodontal disease anywhere, this just doesn’t happen,” said Van Dyke. Additional studies in pigs yielded similar results, and Van Dyke and his colleagues are now conducting a clinical trial on benzo-lipoxin A4-containing mouthwash in patients with periodontitis.

Panel Discussion: Barriers to Translation in Inflammatory Disease

The meeting concluded with a wide-ranging panel discussion  with extensive audience interaction, featuring speakers Godson, Sime, ConteTepper, and Van Dyke, and led by keynote presenter Serhan. Panelists covered issues that ranged from the need for better biomarkers to follow inflammation resolution in laboratory and clinical studies; to the difficulty of overcoming old paradigms of anti-inflammatory interventions in medicine; and the complex interplay between drug-based and “alternative medicine” strategies for promoting inflammation resolution.

Speaker Presentations

Further Readings

Godson

Brennan, E., Wang, B., McClelland, A., et al.

Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis.

Diabetes. 2017; 66(8):2266–2277.

Brennan, E.P., Nolan, K.A., Börgeson, E., et al.

Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1.

J. Am. Soc. Nephrol. 2013;24(4):627–637.

Brennan, E.P., Mohan, M., McClelland, A., et al.

Lipoxins Regulate the Early Growth Response-1 Network and Reverse Diabetic Kidney Disease.

J. Am. Soc. Nephrol. 2018;29(5):1437–1448.

Tepper

Burstein, S.H., and Tepper, M.A.

In vitro metabolism and metabolic effects of ajulemic acid, a synthetic cannabinoid agonist.

Pharmacol Res Perspect. 2013;1(2):e00017.

Motwani, M.P., Bennett, F., Norris, P.C., et al.

Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation.

Clin. Pharmacol. Ther. 2017.

Tepper, M.A., Zurier, R.B., and Burstein, S.H.Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1 activity.Bioorg. Med. Chem. 2014;22(13):3245–3251.

Van Dyke

El Kholy, K., Freire, M., Chen, T., and Van Dyke, T.E.

Resolvin E1 Promotes Bone Preservation Under Inflammatory Conditions.

Front Immunol. 2018;9: 1300.

Viniegra, A., Goldberg, H., Çil, Ç., et al.

Resolving Macrophages Counter Osteolysis by Anabolic Actions on Bone Cells.

J. Dent. Res. 2018;97(10):1160-1169.