this week outline the Biden administration's goals for "Project Next Gen" (PNG), a new $5 billion initiative intended 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 hindered access to the required funds. Details about PNG are not yet available, but we do know it will include efforts to advance vaccines that can counter multiple SARS-CoV-2 variants (or future pandemic coronavirus threats) as well as efforts to develop effective nasally delivered vaccines that might be more efficient at preventing infections than ones given by intramuscular injection.
Many "" vaccines were designed in 2020-2021, as American and international academic research groups rapidly adapted existing methodologies to the COVID-19 pandemic. But 3 years later, very few of the and nasally delivered vaccines have made it into clinical trials, and some high profile concepts seem to have stalled out.
Why is this? The answer is that the basic science involved in vaccine development -- lab-based studies and initial tests in animal models -- is the easy part. The challenging part is vaccine translation: taking a promising concept from the laboratory into early stage human trials. I can say this from personal experience, as I am part of a consortium that moved two (conceptually similar to SARS-CoV-2 S-proteins) from the design stage into . I have also discussed next generation COVID-19 vaccines with colleagues involved in this area as well as other knowledgeable people. (In contrast, creating more broadly active monoclonal antibodies depends more on the discovery stage, as translation into a product is relatively straightforward.)
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 do understand what's involved in translation is essential. That expertise is expensive and hard to find -- the pharmaceutical industry avidly recruits specialists in product translation. A key factor is the need to manufacture vaccine immunogens under the (GMP) conditions required by the FDA for any product to be administered to humans. Navigating the GMP regulations is, to say the least, not simple, and GMP manufacture is very costly. Some vaccine designs that yield immunogens suitable for animal experiments in academic laboratories are difficult to scale-up under GMP conditions. The production process might be too complex, the yields too low, the purification strategies impractical and inadequate.
We have only to look at the long delays faced by the Operation Warp Speed-funded to understand what can happen during vaccine translation. I strongly suspect that such concerns have affected several of the COVID-19 next generation vaccine designs that received media attention over the past 3 years but have not yet made it to humans. Some concepts might be rescuable if PNG can provide the multi-million dollar funding required – and the expertise needed to steer the project to clinical trials.
Nasal vaccine translation is particularly challenging; the mucosal immunology involved is complex; delivery of the immunogen (sometimes with an adjuvant) to humans is not simple; and additional safety considerations must be carefully evaluated.
I was amazed by made this week by cardiologist Eric Topol, MD, in the context of influencing PNG policies at the White House level: "It doesn't take much to get the nasal vaccine across the goal line -- that should be the first priority." That, to me, displays naivety about both vaccine translation and the specific difficulties that apply to delivered . There is, for example, still only one nasal spray influenza vaccine, which has its . One high-profile COVID-19 vaccine has already to meet its endpoints in human trials. None of this is to decry the potential value of a nasal vaccine, or to say that it will be impossible to make a good one. But let's not act as if we are close to the goal line in this area. More likely, we are somewhere around the middle of the gridiron. Whoever runs PNG will need to take a hard look at this complex area of vaccine science when deciding on 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, FDA has reverted to its pre-pandemic norms, where nothing moves quickly. Perhaps PNG can change that attitude for the better.
A major factor is the need to cultivate a greater understanding of immunology than we have seen from the FDA in the past year. Many of the vaccines that will fall under the PNG remit are based on the ancestral 2020 SARS-CoV-2 sequence. may remain a significant , and will need to be factored in. It's also essential that PNG addresses how clinical trials of new vaccines can be carried out in an era when infection- and/or vaccination-naive volunteers will be hard to find for phase I trials, let alone phase III. Immunobridging is an , but FDA has never issued public guidance on what type of datasets it will consider. Several colleagues active in COVID-19 vaccine development have told me how unhelpful this lack of key information has become. A more liberal FDA attitude toward clinical trials outside the U.S. would also help.
The PNG leadership will need to act as Operation Warp Speed did -- by picking potential "winners" when viewed from the vaccine translation perspective, and declining to support concepts, however high profile, that may not be suitable for manufacture under GMP conditions. Tough decisions will likely be needed, and PNG will have to work closely with a hopefully more energized FDA in the way we saw happen in 2020. If all of this happens, there is every chance the $5 billion investment will be money well spent.
John P. Moore, PhD, is a professor of microbiology and immunology at Weill Cornell Medicine in New York City.