Virus World

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m2).

We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies. Epidemiological analyses coupled with immunological phenotyping suggest that humoral immunity induced by COVID-19 vaccines wanes more rapidly in individuals with severe obesity compared to individuals with a BMI within the normal range.

Published in Nature Medicine (May 11, 2023):

https://doi.org/10.1038/s41591-023-02343-2 

Sanofi had previously projected it could produce 100 million doses of vaccine in 2020, and 1 billion doses in 2021. One of the world’s leading vaccine manufacturers has suffered a major setback in its work to produce a Covid-19 vaccine. The problem will push the timeline for deployment of Sanofi Pasteur’s vaccine — if it is approved — from the first half of 2021 into the second half of the year, the company said Friday. The news is not just disappointing for Sanofi and its development partner, GlaxoSmithKline, which is providing an adjuvant used in the vaccine. The companies have contracts with multiple countries, including the United States and Britain, as well as the European Union. Sanofi had hoped to start a Phase 3 trial of the vaccine this month and had projected it could produce 100 million doses of vaccine in 2020, and 1 billion doses in 2021. The problem relates to inadequate results in older adults in Sanofi’s Phase 1/2 trial, which the company traced back to an inadequate formulation of their vaccine, Su-Peing Ng, global medical head for Sanofi Vaccines, told STAT in an interview. Ng said both Sanofi and GSK are committed to continuing work on the vaccine, and plan to begin a Phase 2b trial in February. “We’re disappointed that there is a delay,” she said. “I think, though, that we’re encouraged that we have enough information, enough of the results from preclinical and clinical [studies] to tell us that we have a path forward. We need to optimize this formulation.”

In effect, participants in the trial received too little vaccine. While the too-small dose generated adequate levels of neutralizing antibodies in adults aged 18 to 49 in the trial, adults 60 and older generated lower levels of neutralizing antibodies than are seen in the blood of people who have recovered from Covid-19 infection, Ng said.  Perplexed by the findings, the company set out to figure out why the vaccine underperformed. It discovered two commercial reagents used to measure how much antigen — active vaccine — was included in each dose were giving false readings. In fact, Ng said, the concentration of the antigen “was insufficient.” A revised formulation, tested recently in non-human primates, showed the vaccine prevented damage in the lungs, which is what triggers severe Covid disease in people, and led to rapid clearance of the virus. The vaccine’s path will be more challenging because of this delay; the Covid vaccine landscape is changing daily and placebo-controlled trials may not be feasible for much longer, with the first vaccines soon to be deployed. If people know they may soon have access to an authorized vaccine, there is less motivation to enroll in a trial where they might get a placebo. Sanofi knows this and is proposing to the Food and Drug Administration that its Phase 2b trial compare its vaccine to one that is already authorized, not a placebo. “To continue to provide confidence that we’re going to have a vaccine that meets the expected standard of care, we propose the comparison with an authorized Covid-19 vaccine instead of placebo control,” Ng said. That would set a very high bar for the Sanofi vaccine. Pfizer and Moderna, the front-runners in the vaccine race, have reported vaccine efficacy of about 95% in their Phase 3 trials. If the Sanofi vaccine doesn’t reach that level of efficacy, can it be brought to market, STAT asked Ng.

“That will be up to the regulators,” she said, adding that “for the public to be confident in the choice of a vaccine, it would have to be pretty close to what’s been established now. The Sanofi vaccine would have one advantage compared to the Pfizer and Moderna vaccines: It wouldn’t require ultracold storage and could instead be kept in standard refrigerators, making it easier to distribute Pfizer and Moderna are poised to receive emergency use authorizations from the FDA this month — an FDA advisory panel endorsed the Pfizer shot on Thursday — and vaccine rollout in the United States is expected to begin within days of the FDA’s green light. The Phase 3 trial for Johnson & Johnson’s vaccine — the only one-dose vaccine currently in clinical trials in the U.S. — is about to finish enrollment; if it is effective, it could get an EUA in the first quarter of 2021. The Sanofi vaccine is made with an approach the company uses for one of its flu vaccines, Flubok. That in theory is an advantage; the FDA knows how this vaccine system works. It’s called a recombinant protein vaccine, with the spike protein of the SARS-CoV-2 virus, which cases Covid-19, generated in insect cells. Sanofi is also developing a second vaccine, a messenger RNA vaccine, like the Pfizer and Moderna shots. For this project, it is collaborating with Translate Bio, a Lexington, Mass.-based biotech. Clinical trials for that vaccine have not yet begun.

New research by scientists at the University of Chicago suggests a person's antibody response to influenza viruses is dramatically shaped by their pre-existing immunity, and that the quality of this response differs in individuals who are vaccinated or naturally infected. Their results highlight the importance of receiving the annual flu vaccine to induce the most protective immune response. The researchers found that most of the initial antibodies stimulated after both influenza infections and influenza vaccinations came from old B cells—a type of white blood cell that secretes antibodies—indicating the immune system's memory plays a major role in how the body responds early on to a viral infection. These antibodies displayed higher reactivity toward strains of influenza that circulated during an individual's childhood compared to more recent strains. The study, published December 10, 2020 in the journal Science Translational Medicine, provides those working on a universal influenza vaccine further understanding of how pre-existing immunity affects the development and performance of neutralizing and non-neutralizing antibodies following infection and vaccination. Any effective universal influenza vaccine will depend on scientists identifying 'conserved' parts of the influenza virus that do not mutate over time and that antibodies can target to prevent infection.  "Most interestingly, we found that people who were actively sick with influenza had old antibodies that predominantly targeted parts of the virus that don't change—but those antibodies specifically targeted non-neutralizing sites," said Haley Dugan, co-first author of the study and a Ph.D. candidate in immunology. "When we tested these same antibodies in mice, they weren't able to protect them from being infected with influenza." In contrast, the researchers found that influenza vaccinations boost antibodies that tended to target conserved yet neutralizing regions of the virus, which suggests vaccinations can draw upon pre-existing immunity to prompt more protective responses. Vaccinated individuals also generated many antibodies that targeted new and mutated regions on the virus, suggesting these vaccine-induced antibodies are more adaptable.

Immune system memory ensures a rapid and specific response to previously encountered pathogens. Vaccinations work by exposing the immune system to a small amount of virus, which causes B cells to develop a biological memory to the virus. If the body encounters the same virus later, the immune system is alerted to attack and eliminate the virus.  But in order to be protected, the viral proteins of the infecting strain must typically match those of the strain used in the vaccine. The memory B cells are like keys that fit and bind to the locks—the viral proteins. These memory B cells can survive for decades, providing long-lasting protection from future infections. But if the virus mutates and is significantly different, the memory B cells can no longer recognize the viral proteins, potentially leading to infection. For this reason, the human body is pitted in an evolutionary arms race with the flu. Because influenza viruses rapidly evolve and mutate each season, our immune system has trouble recognizing the viral surface proteins on new influenza strains. As a result, our bodies often rely on old antibodies to fight new influenza strains; this is possible because some parts of the influenza virus that are critical to its structure or function do not change, remaining familiar to our immune system.  Researchers now understand that specific structural and functional parts of the influenza virus that do not change are better for antibodies to target than others. Antibodies that bind to one of these neutralizing sites are able to prevent infection, while antibodies that target non-neutralizing sites often cannot. Scientists believe a person's age, history of exposure to the influenza virus and type of exposure—either through infection or vaccination—all shape whether their immune system antibodies target neutralizing or non-neutralizing sites on a virus.

In the UChicago study, scientists sought to address a major knowledge gap: Which conserved viral sites are preferentially targeted following natural infection versus vaccination in people, and how does pre-existing immunity play a role in shaping the landscape of neutralizing and non-neutralizing antibodies? "For people who have caught the flu, their pre-existing immunity may make them susceptible to infection or increase the severity of their influenza symptoms if their antibodies are targeting 'bad' or non-neutralizing viral sites," said co-first author and Immunology postdoctoral fellow Jenna Guthmiller, Ph.D.  By contrast, vaccination largely induces neutralizing and protective antibodies, old and new, highlighting the importance of receiving the seasonal influenza vaccine.  "This study provides a major framework for understanding how pre-existing immunity shapes protective antibody responses to influenza in humans," said Patrick Wilson, Ph.D., a professor of immunology and lead author of the study. "We need more studies to determine whether the targeting of specific neutralizing and non-neutralizing viral sites directly impacts a person's likelihood of becoming ill." The researchers are now examining how early exposure to the influenza virus in children shapes their immune response later in life as a follow-up to this work.

Cited Research Published in Science Translational Medicine (Dec. 9, 2020):

https://doi.org/10.1126/scitranslmed.abd3601