WAlthough the COVID-19 vaccines currently in use are effective in protecting individuals from severe disease, there are many questions that public health professionals still need to answer about how the shots will be used in the future. What will the effectiveness of a new vaccine version? What is the duration of protection? Is boosters necessary to prolong protection? Are boosters or vaccines more effective and coordinated?
Those were the discussion topics that the U.S. Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee addressed in a day-long virtual meeting on April 6. A 28-member panel of experts examined the data available on vaccine effectiveness to help lay the groundwork for maximising the impact of vaccines on COVID-19.
Because public health experts at the Centers for Disease Control and Prevention (CDC) and regulators at the FDA are still learning about how the virus works, and what type of immunity is needed to control it, the U.S.’s vaccination strategy has relied on a game of catch-up: chasing after waves of infections first with the primary vaccinations and then with booster doses to keep those waves from cresting and overwhelming the health care system with sick patients.
The vaccination schedule, which is complicated based on who gets what vaccines and their age, will continue to be complex for the time being.
Pfizer BioNTech’s mRNA vaccine is, by example, approved for primary vaccination. It can be administered in two doses to adults over 16, and emergency use authorization allows for children under five and 15 years. For anyone above the age of 12, a booster dose should be taken. However, for children aged 5-11 years old, the booster can only be given to those who have a weaker immune system. Moderna’s mRNA vaccine has been approved for adults 18 years and older as a 2-dose primary vaccination. A third booster dose is also available for those of this age. The Johnson&Johnson-Janssen vaccine is authorized as a single primary vaccination with a second booster dose for adults 18 and older.
The FDA also recently authorized a second booster dose (fourth shot) of both Pfizer-BioNTech’s and Moderna’s vaccines for people over age 50 and those with compromised immune systems.
Because of these complicated guidelines, FDA called its committee together to devise a more efficient and systematic vaccination strategy. Currently, 70% of the U.S. population that is eligible to get vaccinated has received their primary immunization—two doses of mRNA vaccines from Pfizer-BioNTech or Moderna, or one dose from Johson&Johnson-Janssen. A mere 50% of these people have had a booster shot.
Studies show that vaccine boosters and primary doses of vaccines do not provide the same immunity as the original recommendations. Panelists heard from CDC scientists who stated that blood serum taken from full-vaccinated people was tested for the Omicron variant. This resulted in a 25-fold decrease in neutralizing antibodies. A 6-fold reduction was observed in those who received boosters.
That means the current booster strategy isn’t sustainable, so the committee discussed ways to establish a more structured plan for studying vaccine effectiveness and making decisions about whether, and when to change the shots or boosters.
They discussed the influenza model. The annual flu shot is an opportunity for a panel of experts from the World Health Organization to analyze the data about the genetics of influenza viruses and how they are causing disease. These experts then suggest which strains of influenza should go in an annual shot. This advice is generally followed by health authorities in different countries when they make their flu vaccines.
That model isn’t entirely applicable to SARS-CoV-2, since researchers don’t fully understand its genetic changes and what they might mean for causing human disease. Alpha, Beta, Delta, and Omicron are all variants of the original virus. They do not show any predictable pattern. That’s very different from the influenza virus, which generally does change in broadly predictable ways.
In addition, while most flu vaccines are built the same way, by growing the desired influenza strains in chicken eggs and then generating specific flu proteins to include in the shots, there’s a range of approaches used in COVID-19 vaccines, with some relying on mRNA, some on recombinant viral proteins, and still others on viral vectors to deliver viral messages to the immune system.
Further, with COVID-19, it isn’t clear that an annual vaccine like the influenza approach would make sense, But what would drive that change isn’t entirely obvious either. “The issue of how we decide when the vaccine needs to be modified, and what is going to be the threshold where we say so much escape from vaccine immunity requires a change—that’s such a difficult question to answer,” said Dr. Cody Meissner, director of pediatric infectious disease at Tufts Medical Center, and one of the FDA committee members.
For practical reasons, such decisions may have to use data that is not the standard of excellence that committee members prefer. Safety and clinical testing would be required for any new vaccines. The ideal scenario would involve months of long studies that included people exposed to the virus and then vaccinated. This will allow us to assess how sick and dangerous they are.
However, in order to ensure enough vaccines are available for fall cases, the shots would have to be ready by May/June. The committee discussed using lab-based research to determine if the vaccines are effective in neutralizing the virus.
These studies are ongoing. COVAIL was recently initiated by the National Institute of Allergy and Infectious Diseases. This is one that the committee will be closely monitoring. The trial, which will investigate different booster doses—and versions—of Moderna’s mRNA COVID-19 shots, involves 600 participants at 24 sites across the US. The volunteers were vaccinated twice with Moderna and once with a booster. One of six boosters will be given to them:
- A second dose of the vaccine
- A dose of experimental shots targeting the Beta and Omicron versions
- Two shots of the experimental vaccine against Omicron, Beta, and Omicron were administered two months apart.
- A dose of experimental shots targeting Omicron and Delta
- A dose of Omicron-targeting experimental vaccine
- A dose of experimental vaccine that targets the Omicron strain.
“Could we come up with a strategy where we are not chasing variants but could make a vaccine that targets a cocktail of variants?” says Dr. Nadine Rouphael, professor of medicine and executive director of the Hope Clinic at the Emory Vaccine Center, and co-chair of the COVAIL study. “The idea behind COVAIL is to take the available variant vaccines, either alone or in combination, and try to see how the immune responses they generate compare against the [original] vaccine.” Rouphael expects early results sometime this summer. Other similar studies involving Pfizer-BioNTech’s mRNA vaccine are also under way and will provide results in a few months as well.
The current policy of responding to COVID-19 waves with another booster dose “will not get us what we ultimately want, which is basically a vaccine that is more durable and more cross-protective,” says Rouphael. A vaccine that is effective against multiple strains of the virus at the same time, and which can also offer longer-lasting immunity, was the consensus among the panel.
Additionally, the committee stressed the need for FDA to play an active role in developing vaccines, rather than waiting on pharmaceutical companies. “Now we have the manufacturers coming to us with proposals for how to evaluate the composition and strain of the vaccines,” said Jerry Weir, director of viral products in the FDA’s Office of Vaccines Research. “What about the idea that we better coordinate in advance what studies need to be done to inform strain selection?”
In order to be more knowledgeable about the future of the COVID-19 vaccine program, the FDA was asked by the committee to give them all the information they can on COVAIL studies and SARS-CoV-2 genetic mutations that scientists are following. “What keeps me up at night is the knowledge that we can’t keep boosting. We’re going to have vaccine exhaustion, and I’m not talking about immune exhaustion but physical exhaustion from people who won’t get boosted,” said Dr. Peter Marks, director of the Center for Biologics Evaluation and Research at the FDA. “We want people to remain confident in the safety and effectiveness of all COVID-19 vaccines. Our goal is to stay ahead of future variants and outbreaks to ensure we do our best to reduce the toll of disease and death due to COVID-19 on our population.”
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