Wayne Koff is the founding President and CEO of the Human Vaccines Project (HVP). He has decades of experience in vaccine development and may also soon be a trial volunteer, having signed up to participate in future COVID-19 vaccine studies. Koff is also an Adjunct Professor of Epidemiology at the Harvard T.H. Chan School of Public Health (HSPH), which is partnering with the HVP to decipher what effective immunity is in ageing adults. HVP Editor Kristen Jill Abboud recently discussed the state of COVID-19 vaccine research with Koff and asked him about the priorities for evaluating and deploying eventual vaccines in various populations, including the elderly.

An edited version of the conversation appears below.

What are the most critical unanswered questions about immunity to this novel coronavirus?

The major unanswered question is: what causes the wide breadth of pathogenesis we see with this virus in different age groups and in different populations? What is at the root of that? Within that, there are specific questions about pathogenesis within the elderly. We’re learning more and more that people have a chronological age, but they also have a biological age, and most likely also an immune age. We have the capacity now with the tools at our disposal—tools of systems biology, all of the ‘omics’ assays, and advances in artificial intelligence and machine learning—to really understand this immune age in ways we couldn’t possibly have just a few years ago. It is conceivable that there are 80-year-olds whose immune systems are as robust as a 40-year-old, and vice versa. This may play into why some people infected with SARS-CoV-2 are asymptomatic, some have mild disease, some have severe disease, and others die.

Another important question involves looking at natural infection in different places. There was obviously a concern that there was going to be a huge COVID storm in Africa. That has not played out yet. Some people say that this is just because of a lack of surveillance, but there may be other issues going on there. It is a younger population, but then there are many other issues, including concomitant infections and differences in microbiome. Understanding these differences in the pathogenesis of SARS-CoV-2 infection is going to be really important.

There is also the question about what impact pre-existing immunity from prior infection with other coronaviruses has on the pathogenesis of the disease, or with respect to vaccination: is it good, bad, or indifferent? We’re beginning to look at this with regard to the impact on the immunogenicity and efficacy of COVID vaccines with our colleagues Shane Crotty and Alex Sette at the La Jolla Institute of Immunology.

What are the biggest outstanding questions with regard to vaccines?

Once you get past the question of whether they are going to work, one of the biggest questions is how well they will work in the elderly and other vulnerable populations, including those living in low-resource settings. If you look at the early vaccine trial data, it looks like, in general, the elderly adults are not making as high titers of neutralizing antibodies as the younger adults. We don’t know what the cutoff is in terms of the neutralizing antibody titer you’re going to need for the vaccine to be effective, but certainly when you think about the durability of the vaccine-induced immune responses, you’re going to end up below that threshold faster if you begin at a lower level.

What do you see as the best-case scenario for the first generation of COVID vaccine candidates?

There are three scenarios, using a baseball analogy: the homerun, the single, and the strikeout. The homerun is you get a vaccine that is 90% or more effective, works across all the ages, and is durable. I think that’s unlikely to happen. Similarly, I don’t think the strikeout analogy—the case where there is no or limited efficacy or even immune enhancement that would not only squelch one vaccine candidate but have an impact across all vaccine efforts—is likely.

There are plenty of reasons to be cautiously optimistic about vaccines based on the animal data, the early human data, and the monoclonal antibody studies. The most realistic scenario is that one or more of the vaccines now in efficacy trials has an efficacy of at least 50%. This level of efficacy should get it over the line for licensure or Emergency Use Authorization. It would be even better if it reached that bar and worked equally well across different age groups. It would be unfortunate if we end up with a situation like we have with the influenza vaccine, which is about 60% effective in kids or young adults and is often only 30% effective in the elderly.

So far it looks like the vaccine responses for the candidates furthest along in development are relatively similar—I don’t think any of them are really hitting it out of the park. It doesn’t look like they are doing as well in the upper respiratory tract as they are in the lower respiratory tract, which is why the efficacy trials have prevention of disease as a primary endpoint and not prevention of infection.

How will vaccines be prioritized if multiple candidates show similar levels of efficacy?

Well, first of all, they aren’t all going to finish efficacy studies at the same time. And we won’t immediately know what immune responses correlate with efficacy. Once we do have a correlate, the question is whether bridging studies will be required for the other vaccine candidates. If so, how do you plan for that? Will you roll out a couple of vaccines at once? Will they all work equally well in the high-risk groups, which is what you will be looking at, at least initially?

Other candidates that are behind in development may offer additional benefits but there are still many questions about how they will get evaluated. Can you still run a placebo-controlled trial after some of the earlier vaccines are in use? These are all questions that regulators will have to address. Another interesting question is what will happen if you do have a highly effective vaccine, because then there will be pressure to vaccinate all of the placebo recipients and then you no longer have a placebo-controlled trial for long-term follow up.

What are the highest priorities for manufacturing and implementation of effective vaccines?

Historically, in terms of deployment, the target of the vast majority of vaccines are infants and children and we don’t do as well with all of our other vaccines that are delivered to adults and the elderly. The influenza vaccine isn’t even offered in many countries and uptake in the U.S. is around 50%. There is a learning curve here and I think we will need to do demonstration projects with existing vaccines to learn how to deliver them more effectively to adults and the elderly in both developed and developing countries. That is one priority.

Another is documenting how much manufacturing capacity exists for each of the vaccine platforms—nucleic acid, recombinant proteins, synthetic peptides, viral vectors, live-attenuated, and whole inactivated—and how many doses can be reasonably expected by the middle and end of next year, which is going to impact the prioritization of the deployment.

The last issue really is where we go from here. COVID has shown us how unprepared we are, as a world, to face a pandemic. There has been an unprecedented response to this virus—the idea of going from a concept to a deployed vaccine in 18-24 months was unthinkable just a few years ago. The global community has responded, by building on vaccine platforms developed for HIV, TB, and malaria vaccines, coupled with newly established organizations such as CEPI, Gavi, and others, and this has enabled a rapid response. With that said, before this is all over hundreds of millions of people are going to be infected and millions are going to die. The lesson here is to get in front of the curve. The question is how do we do that? It’s not a question of if, but when the next coronavirus is going to emerge. One of the biggest priorities is what we can learn that is going to leave us better prepared so that the next time millions of people don’t have to lose their lives, and millions more don’t need to lose their livelihoods because the global economy crashes in response to a pandemic.

Interview by Kristen Jill Abboud