Media reports this week outline the Biden administration’s goals for “Project Next Gen” (PNG), a new $5 billion initiative that aims to create better vaccines and monoclonal antibody treatments against COVID-19. In an ideal world, such a program would have been put in place a year or two ago, but domestic politics impeded access to the necessary funds. Details about PNG are not yet available, but we do know that it includes efforts to advance vaccines that can combat multiple SARS-CoV-2 variants (or future pandemic coronavirus threats) as well as efforts to develop effective nasally delivered vaccines. More efficient in preventing infection than given by intramuscular injection.
Several “next generation” vaccines were designed in 2020-2021, as US and international academic research groups rapidly adapted existing methods to tackle the COVID-19 pandemic. But 3 years later, very few pan-coronavirus and nasally-delivered vaccines have made it into clinical trials, and some high-profile concepts appear to have stalled.
Why is this? The answer is that the basic science involved in vaccine development — laboratory-based studies and preliminary tests in animal models — is the easy part. The challenging aspect is vaccine translation: taking a promising concept from the laboratory to early-stage human trials. I can say this from personal experience, as I was part of a consortium that moved two HIV-1 envelope glycoprotein vaccine antigens (alternatively similar to SARS-CoV-2 S-proteins) from the design phase to ongoing clinical trials. I have also discussed next-generation COVID-19 vaccines with colleagues and other knowledgeable people involved in the field. (In contrast, more broadly active monoclonal antibodies depend more on the discovery phase, since translation into production is relatively simple.)
When it comes to vaccine translation, academic researchers generally don’t know what they don’t know — but need to know in order to make progress. It’s a whole new world, and one with a steep and painful learning curve. Access to skilled help from people who understand what translation entails is essential. That expertise is expensive and hard to find — the pharmaceutical industry hires experts in product translation. A key factor is the need to manufacture vaccine immunogens under good manufacturing practice (GMP) conditions that are required by the FDA for any product to be administered to humans. Navigating GMP regulations is not simple, to say the least, and GMP manufacturing is very expensive. Some vaccine designs that produce immunogens suitable for animal use in academic laboratories are difficult to scale up under GMP conditions. Production processes may be too complex, yields too low, purification strategies impractical and inadequate.
We need only look at the long delays faced by the Operation Warp Speed-funded NovaVax COVID-19 vaccine to understand what can happen during vaccine translation. I strongly suspect that such concerns have affected the next-generation vaccine designs for COVID-19 that have received media attention over the past 3 years but have yet to make it to humans. Some concepts may be salvageable if PNG can provide multi-million dollar funding – and Expertise required to take the project to clinical trials.
Nasal vaccine translation is particularly challenging; The mucosal immunology involved is complex; Delivery of an immunogen (sometimes with an adjuvant) to humans is not simple; and additional security considerations should be carefully evaluated.
I was struck by a comment made this week by cardiologist Eric Topol, MD, regarding influencing PNG policies at the White House level: “It doesn’t take much to get a nasal vaccine to the target line — that should be the first priority.” This, to me, shows naivety about both vaccine translation and the particular difficulties that apply to nasally delivered vaccines. There is, for example, still only a nasal spray influenza vaccine, which has its limitations. A high-profile COVID-19 vaccine has failed to meet its endpoints in human trials. None of this is to denigrate the potential value of nasal vaccines or to say that it would be impossible to improve. But let’s not act like we’re close to the finish line in this area. Most likely, we are somewhere in the middle of the gridiron. Anyone running PNG needs to take a hard look at this complex area of vaccine science when deciding what to prioritize.
In 2020, the FDA showed a refreshing “can-do” attitude when working with Operation Warp Speed, helping to create strategies that led to the authorization of COVID-19 vaccines within that calendar year. Since then, the FDA has returned to its pre-pandemic standards, where nothing moves fast. Perhaps PNG can change that attitude for good.
A key factor is the need to cultivate a greater understanding of immunology than we saw from the FDA last year. Many vaccines that fall under the PNG remit are based on the 2020 SARS-CoV-2 sequence. Immunity seals can remain a significant performance limitation, and need to be addressed. PNG also needs to address how clinical trials of new vaccines can be conducted in an era where infection- and/or vaccine-preferred volunteers are difficult. Look for phase I trials, let alone phase III. Immunobridging is an obvious answer, but the FDA has not issued public guidance on what types of datasets it will consider. Many colleagues active in COVID-19 vaccine development have told me how unhelpful this lack of key information is. A more liberal FDA approach to clinical trials outside the United States would also help.
PNG leadership needs to act as Operation Warp Speed did — picking potential “winners” when viewed from a vaccine translation perspective, and refusing to support concepts, however high profile, that may not be suitable for manufacturing under GMP conditions. Tough decisions are likely to be required, and PNG will have to work closely with a hopefully more energized FDA in the way we see in 2020. If all this happens, the $5 billion investment is likely to be well spent.
John P. Moore, PhD, is a professor of microbiology and immunology at Weill Cornell Medicine in New York City.