The advent of mRNA vaccines against SARS-CoV-2 have been nothing short of a modern medical marvel. Billions of doses have been safely administered and countless lives saved. But a recent request by Moderna to the FDA to authorize a second booster -- or fourth dose -- for all adults has been met with skepticism by many of us in public health and medicine.
Multiple countries, including the U.S., recently joined Israel in authorizing a fourth dose of the mRNA vaccines for older members of their populations and others at risk of severe COVID-19. While this makes immunological sense -- as older people and the immunocompromised can lack the ability to quickly mobilize B cells to produce neutralizing antibodies when faced with new variants -- a fourth dose in younger, healthy groups (<65 years) has minimal effect in both boosted effectiveness against infection or reducing viral loads. The FDA's recent authorization of a fourth shot for those over 50 (citing "significant medical comorbidities" in those 50-65) is not in line with our available data nor other countries' policies. This unilateral decision by the FDA was also made without consulting its committee of independent vaccine experts, who are slated to meet April 6 to discuss our overall booster strategy.
As the COVID-19 vaccine campaign continues, we are concerned that despite continued promises to "follow the science," our health agencies, including the FDA and CDC, and the Biden administration continue to act without clearly articulating strategic, evidence-based goals for both the vaccine and subsequent boosters.
Clarify the Goal
First and foremost, our country needs to specify the goal of our vaccination and booster campaign. Is it to continually boost neutralizing antibody protection against infection? Or is it to prevent severe illness and thus reduce the burden on our healthcare system? The former strategy is logistically difficult, will lack buy-in from a pandemic-weary public, and does not make long-term immunogenic sense. The latter is a much more feasible and public health-focused strategy.
While President Biden has mentioned the booster goal of preventing severe COVID-19 in speeches, this has not been formally articulated and advertised as the primary aim. In alignment with this goal, we need to expand our vaccine and booster arsenal to prepare for variants that could cause more widespread severe illness.
Expand the Vaccine Arsenal
In the U.S., our COVID vaccine arsenal is limited to two mRNA vaccines and one adenovirus vector-based vaccine, all showing our immune systems a piece of the SARS-CoV-2 spike protein. For future boosters, given the inevitable emergence of new variants of concern (VOC) with mutations across the virus, including many in the spike protein, we need to show our immune system something more broad ranging. The FDA needs to conduct more research on and approve an inactivated whole virion vaccine.
Enter Covaxin. There are currently three inactivated whole virus vaccines approved by the World Health Organization (WHO): Covaxin, which was originally developed in India but now has a U.S. manufacturer called Ocugen, and Chinese-developed Sinopharm and Sinovac. Of these three, WHO has deemed Covaxin the most immunogenic. Covaxin's advantage could be due to its adjuvant, Alhydroxiquim-II, developed with funding by the NIH. Alhydroxiquim-II plays a key role in activating lymph node receptors, which boosts the immune response and enhances the vaccine's effectiveness.
Because Covaxin shows the immune system the entire virus, the vaccine elicits a broad immunologic response not only against spike, but also against the receptor-binding domain, the nucleocapsid protein of SARS-CoV-2, and other parts of the virus. The vaccine also elicits strong cellular T-cell mediated immune responses, which are vital for long-term protection. Because these immune responses are so broad, they are active against known variants of concern (VOC). The phase III study of this vaccine in India showed a high protective efficacy against SARS-CoV-2, with 93.4% protection against severe disease -- healthcare workers in India who received Covaxin well into the Delta variant era have continued to be highly protected. While the two mRNA vaccines showed reduced effectiveness against Omicron (for mild disease) due to Omicron's 32 mutations across its spike protein, immune responses from the Covaxin vaccine continued to neutralize the Omicron variant.
Covaxin has also been tested in a younger cohort of participants (2-18 years old) in India. A phase II/III, open-label, multicenter study was conducted from May 2021 to July 2021, to evaluate the safety, reactogenicity, and immunogenicity of the vaccine in this group. The results showed excellent immune responses across the entire cohort. Moreover, among the 526 study subjects in the pediatric clinical trial, no serious adverse effects were reported. Safety evaluations in adults after the administration of over 59 million doses or children 15-17 after over 36 million doses have similarly found no major adverse effects. Seemingly due to a lack of U.S. research on Covaxin, the FDA rejected an application by Ocugen to approve Covaxin for those 2-18 years old earlier this month.
A VOC can develop mutations across multiple parts of its surface, often to increase transmissibility. As we continue to manage SARS-CoV-2 into the future, given the inability to eradicate the virus, we will need to see the whole virus to boost our immunity against variants. Whole virion vaccines, like Covaxin, can neutralize the Delta and Omicron variants.
We strongly recommend our public health agencies and the Biden administration closely follow the recently launched U.S.-based study on the safety and efficacy of whole virion vaccines as a booster. If the results are positive, we must add these vaccines to the U.S. vaccine arsenal, as both a booster for those who have received mRNA vaccines and also as a strong primary series vaccine for those yet to be inoculated.
Another important tool the U.S. should add to its vaccine arsenal is Novavax. Novavax is a protein subunit vaccine, similar to flu vaccines and those for many routine childhood immunizations -- this more traditional vaccine technology could help some overcome vaccine hesitancy. In the U.S., vaccine hesitancy ranges from less than 2% to more than 20% depending on zip code and county. In some states, 14% of those hesitant are concerned about possible side effects and approximately 6% cited "planning to wait and see if it's safe" as of February 2022. Expanding our arsenal to include non-genetic material platform vaccines would go a long way toward addressing these concerns, however unfounded they are. In a phase III trial in adults, two doses of the Novavax vaccine were 90.4% effective against symptomatic infection and 100% effective against moderate and severe disease, although more study in the Delta and Omicron era are needed. Novavax is approved by the WHO and is awaiting U.S. EUA.
The FDA should seriously consider these other vaccine technology platforms. For this evolving virus, showing the immune system the entire virion may be indicated sooner rather than later to prepare for future variants, and more familiar technology can protect our hesitant populations from severe COVID-19 disease.
Monica Gandhi, MD, MPH, is a professor of medicine in the school of medicine at University of California, San Francisco. Michael Daignault, MD, is an emergency physician at Providence Saint Joseph Medical Center in Burbank, California.
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