Thursday, March 25, 2021

How are COVID-19 vaccine developers and regulators responding to variants?

By Lisa Larrimore Ouellette, Nicholson Price, Rachel Sachs, and Jacob S. Sherkow

The remarkable news of record-breaking COVID-19 vaccine development has been clouded by the increasing emergence of new variants of the SARS-CoV-2 virus. Like other viruses, SARS-CoV-2 mutates over time, due to random errors in copying its genetic sequence. When one of these mutations helps the virus survive and reproduce—such as by making the virus more transmissible—that variant will spread more rapidly than the original virus through natural selection. The global effort to control the pandemic has thus been framed as a race between the vaccines and the variants: can the world be vaccinated before the virus evolves to evade the vaccines? In this post, we examine how COVID-19 vaccine developers are responding to the spread of variants, how the FDA plans to regulate updates to the vaccines, and other innovation policies governments should consider to combat the variant spread.

How are COVID-19 vaccine developers responding to variants?

As SARS-CoV-2 variants sweep the globe, a critical question is whether the currently authorized vaccines provide protection to individuals who come in contact with those variants. Answering that question in the field is difficult, but three vaccines (including Johnson & Johnson’s) showed lower efficacy in clinical trials conducted in South Africa (origin of the more transmissible 501Y.V2 variant) than in other locations. Clinical trials for the two mRNA vaccines authorized in the US (from Pfizer–BioNTech and Moderna) were completed before the more recent variants became widespread, so researchers have leaned on in vitro analyses instead—measuring how well the blood serum of vaccinated individuals performs in reducing live viral “plaques.” The most detailed summary to date of this in vitro evidence reports that the Pfizer–BioNTech and Moderna vaccines show markedly decreased plaque reduction activity against the three most common variants: B.1.1.7 (first reported in the UK), 501Y.V2 (first reported in South Africa), and P.1 (first reported in Brazil). (There’s not enough data yet on J&J’s vaccine.) Translating these decreases in activity to measures of actual protective ability are difficult, for a variety of practical and immunologically complex reasons. Nonetheless, the in vitro data is not good news. 

If existing or novel SARS-CoV-2 variants escape the immunity conferred by current vaccines, hope may lie in modifying vaccines to target the variants. All of the currently authorized vaccines in the US and Europe prime the immune system to respond to one specific protein on the outside of the SARS-CoV-2 capsid, the “spike” protein, named so for the crown-like spikes sticking out from the surface of the virus that give coronaviruses their name. All of the variants thus far seem to modify this spike protein. Moderna and Pfizer–BioNTech’s vaccines provide an mRNA copy of the spike protein to be produced by the body’s immune cells, thus generating a response. J&J and AstraZeneca do the same, but with DNA.

Adjusting these mRNA or DNA sequences is relatively easy, and so developers can—in theory—adjust their vaccines to target these variants by simply encoding for the variant sought to be targeted, or producing a blended version that contains mRNA or DNA copies of both the “old” SARS-CoV-2 variant and newer ones (a “multivalent” vaccine). The way the currently authorized vaccines are made, these changes would be slightly easier for Moderna and Pfizer–BioNTech. For J&J and AstraZeneca, the science is similarly straightforward but takes about twice as long (3 months). And this doesn’t account for the additional challenge that individuals could, over time, develop immunity to the particular vector used by the two manufacturers (a modified adenovirus).

Developers are aware of these possibilities and most have announced plans to adjust their vaccines to incorporate these variants. Moderna, the first firm to have a vaccine candidate ready for testing in early 2020, was also the first to announce a candidate for variants on January 25 of this year. On February 24, it announced it was ready to begin its variant-based clinical study as soon as regulators approve the trial. BioNTech, meanwhile, said it could adjust its vaccine in about six weeks. Both modified vaccines would need additional time for testing and manufacturing before they could reach the public. In the meantime, on February 25, Pfizer and BioNTech began to study the effects of giving already vaccinated individuals a third booster dose of their existing vaccine. J&J is also working on updated versions of its vaccine. And researchers are considering ways to make vaccines more resilient in the first place rather than requiring constant redesign. Despite the global spread of variants, there may be a silver lining in that this move toward innovative vaccine “updating” may “not only tackle viral variants but also provide solutions across the globe at a fraction of the cost.”

How does the FDA plan to regulate vaccines for variants?

The typical regulatory process of approving a new vaccine requires three phases of randomized controlled clinical trials, lasting several years. The length of this process cannot compete with the speed of virus mutation, and even the compressed timeline within which COVID-19 vaccines initially came to market is likely to be too slow. As a result, there is a need to consider whether additional regulatory approaches can be used to speed vaccines for variants to market. Particularly where a given vaccine approach has been rigorously demonstrated to be safe and effective against one form of a virus through this randomized trial process, regulators may use other types of clinical evidence to evaluate the efficacy of a slightly modified version of that vaccine.

On February 22, the FDA released new guidance for medical products related to SARS-CoV-2 variants, including an updated version of their existing vaccine guidance. The guidance describes the required nonclinical and clinical data the FDA expects to use in evaluating the efficacy of vaccines targeted against emerging variants, including clinical studies that compare an immune response to variants induced by the modified vaccine against an immune response to the authorized vaccine. The agency directs sponsors to perform studies on individuals who have not yet received a COVID-19 vaccine as well as on those who received the authorized vaccine (for whom the new vaccine would be a booster shot).

The FDA’s guidance document for vaccines targeted at SARS-COV-2 variants is not exhaustive, though, and questions remain to be answered. In particular, the guidance notes that it “does not address how it will be determined that a vaccine based on a new viral sequence is needed.” FDA’s Acting Commissioner, Dr. Janet Woodcock, did not give specific criteria as for how the agency would determine when such an update was needed. At a news briefing, she emphasized the need to “to anticipate this and work on it so that we have something in our back pocket before the threshold is upon us.”

Using immunogenicity assessments (rather than full-scale clinical trials) to evaluate vaccines modified to address virus variants is not a new endeavor for the FDA. The seasonal flu vaccine is regulated in much the same way—vaccine manufacturers use already-proven methods and platforms and adapt them for the flu virus strains projected to be circulating in the upcoming season. The agency has specifically issued guidance for pandemic flu situations, instructing manufacturers of existing licensed seasonal flu vaccines as to the immunogenicity studies they would need to complete before manufacturing a pandemic influenza vaccine using the same process. Professor Amy Kapczynski has written about the ways in which much of the information regarding flu virus strains moves through a global virus-sharing network, using open science rather than traditional exclusivity models. Learning from these models may help reduce the cost of developing—and distributing—modular vaccines, hopefully decreasing some of the inequities currently present in global vaccine distribution.

What other policies should innovation policymakers consider to address variants?

Authorizing developed variant vaccines is not the only task for policymakers, who should consider several other routes to keeping variants at bay. Not all the action is at the FDA, even though it undoubtedly plays a central role. Other health-related policy interventions would be useful in understanding variants and limiting their spread, better understanding different vaccine options for variants, and improving vaccine performance once vaccines are developed.

The best way to deal with new and troubling variants is to avoid their development in the first place. While policymakers can’t control how the virus evolves, they can help limit the chances it has to do so—and that means ramping up production and distribution of vaccines globally. Uncontrolled spread results in more variants, including those which can evade existing vaccines or reinfect the already infected. Pushing for rapid, complete vaccination across the globe is thus not merely the right moral and ethical approach; it’s also important from a purely self-interested perspective of countries with vaccine supply. Interventions we have suggested in prior work, including sharing manufacturing know-how with other manufacturers, would help these efforts and, consequently, decrease the chance of future variant development.

Once variants exist, it is important to know what, where, and how widespread they are. This means genetic surveillance—sequencing infected patients to know which variant they have contracted. Genetic surveillance is a problem of nonexcludable innovation, which suggests that private actors are unlikely to spend enough on it, leaving governments to fill the gap. Some governments do genetic surveillance very well; the United States doesn’t, at least nationally. Such surveillance should also help scientists understand how effective existing vaccines are in managing the spread of variants. 

Better understanding the performance of vaccines suggests its own potential policy intervention. Each vaccine was tested in a different time frame, with different populations, in different places, and—crucially—with different variants at different levels circulating in the population. As a result, despite headlines trumpeting different vaccine performances (and some policy reactions), no one really knows whether Johnson & Johnson’s or AstraZeneca’s vaccines are actually less effective than Moderna’s and Pfizer–BioNTech’s. Even less is known about how a vaccine modified to address a variant would compare with any of them. Running comparative randomized controlled trials between multiple different vaccines seems unlikely—indeed, comparative trials are underfunded generally—but at the very least policymakers should consider robust systems for collecting observational data to understand how different vaccines perform. 

Once vaccines are approved, getting them made remains a challenge—and with variant vaccines, that challenge will continue. Flexible manufacturing platforms should make it easier to get variant vaccines into scaled-up production more rapidly, and further investment in such platforms could help with that challenge. As we’ve noted, older processes to manufacture vaccines were materials intensive—some involve incubating viruses in chicken eggs. mRNA vaccines, on the other hand, are less resource intensive and seem especially well suited to variants, since the encapsulated mRNA sequence can be easily altered without changing other production parameters. Government efforts to improve manufacturing generally, and especially around mRNA or other flexible manufacturing platforms, could be essential to producing variant vaccines if COVID becomes endemic and continues to change. 

Finally, getting vaccines into arms is always the last step, without which nothing matters; investing in better vaccine roll-out is essential if variant boosters will become routine. An example for this exists, of course: the annual flu vaccine. Someday we all may get annual COVID vaccines, tailored to that year’s new variants. But for that to work, the health system would need to do a better job keeping track of who gets what, whether first and second vaccine shots can be mixed and matched, and how to insure that ongoing distribution is efficient, affordable, and equitable. 

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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