Project Syndicate: Last year, you wrote that, “Deliberately infecting healthy human volunteers with the SARS-CoV-2 virus in order to test the efficacy of potential COVID-19 vaccines is unnecessary, uninformative, and unethical,” warning that doing so could end up “destroying trust in the integrity of science and medicine for generations to come.” More recently, reports of rare blood-clotting disorders linked to the Oxford/AstraZeneca and Johnson & Johnson vaccines have similarly been undermining public trust. Do such developments fuel support for human challenge studies?
William A. Haseltine: No. The blood clots are so rare that they wouldn’t even appear in a human challenge study, which by design would test the vaccines on a very small group of people – usually no more than 20 to 100 – who are entirely healthy. Obtaining appreciable numbers of people with adverse side effects would require testing several million.
In other words, there simply isn’t sufficient justification for human challenge studies. Why scientists and doctors would pursue them, much less grant them ethical permission, is a mystery.
PS: You have often highlighted the limitations of even the most effective COVID-19 vaccines – a challenge you address in detail in your new book, Variants! The Shape-Shifting Challenge of COVID-19. And yet some hope to be able to develop a single vaccine for all coronaviruses, including those that may emerge in the future. Given the challenges of vaccinating against coronaviruses, is it a promising investment? Or should we be focusing our attention – and resources – on other health interventions?
WAH: An urgent priority should be for an international institution – preferably the World Health Organization – to issue reports containing detailed data on the safety and efficacy of vaccines against each and every SARS-CoV-2 variant of interest. These data should come from real-world vaccination reports, rather than laboratory studies. Moreover, since the protective effects of all vaccines will likely wane over time, it is just as essential that we monitor vaccine efficacy in infected individuals over time, as well as potential long-term adverse events.
PS: While vaccines have been capturing much of the world’s attention, researchers have also been hard at work developing new and innovative treatments. In December, you pointed out that many once-promising approaches had proved ineffective, and those with “greater therapeutic potential,” like monoclonal antibodies, were still “many months away.” Five months later, are there any new approaches that you find particularly interesting or promising?
WAH: I’m pleased to say that great progress has been made with monoclonal antibodies. Cocktails of monoclonal antibodies have recently been shown to prevent COVID-19 transmission in congregate living situations. If used early enough – immediately after the first presentation of symptoms – monoclonal antibodies can also substantially reduce the incidence of severe symptoms.
Unfortunately, none of the original monoclonal antibodies is effective against the virus variants. But, in recent months, there have been reports about new antibodies and nanobodies that are effective against many, though not all, potential variants. Proper use of monoclonal antibodies for prevention and treatment requires knowledge of which variants are spreading and where they are prevalent. That, in turn, demands a massive expansion of our surveillance and sequencing capabilities. My recommendation is that every patient who receives therapy with monoclonal antibodies has the sequence of the infecting virus determined, as is the case with HIV.
There is also good progress being made in development of so-called small-molecule antiviral drugs. These include Molnupiravir, a polymerase inhibitor, and several new inhibitors of the major protease. One new protease inhibitor developed by Pfizer appears to be promising.
Another bit of excellent news is the discovery that many of the approved hepatitis C drugs, which are available at very low cost in many counties, inhibit the minor protease – the product of the SARS-CoV-2 virus’ Nsp3 protein. Moreover, they are potently synergistic with remdesivir (a broad-spectrum antiviral medication, and the first drug the US Food & Drug Association approved for treating the SARS-CoV-2 virus). I suspect the same will be true for other polymerase inhibitors, such as Molnupiravir. These combination drug therapies will complement existing prevention and therapeutic strategies for control of COVID-19 infection and disease.
PS: Ultimately, you argue, there is no quick medical fix for COVID-19. In fact, in your view, the biggest lesson of 2020 is that “public-health measures that are stringently applied through strong leadership, governance, and social solidarity can quickly bring a pandemic under control and limit the death toll.” To what extent has this approach been adopted by national leaders, and how could such policies be coordinated to address a global contagion?
WAH: I regret to say that, to our great misfortune, the fundamental lessons have not been systematically applied. In the case of the United States, we’ve relied solely on vaccines, rather than simultaneously pursuing other much-needed public-health measures. One without the other is a recipe for continued trouble, both nationally and internationally. That is why General John R. Allen, President of the Brookings Institution, and I have called for a bipartisan commission to look into not only the mistakes we’ve made, but also what we can do to avoid such errors in the future, as this pandemic is certain to continue – and new pandemics are sure to follow.
PS: One notable area where the pandemic has given medical science a push is in the development and use of mRNA vaccines. What are the advantages of these vaccines? Are they the future of vaccinology?
WAH: The effectiveness of mRNA vaccines – and the speed at which they were developed – has been nothing short of miraculous. They are by far the safest and most effective vaccines, with the fewest adverse events. It is the right technology for the right disease.
This type of vaccine has the further advantage that it can be modified very rapidly to create boosters targeting circulating variant strains – for example, the B.1.1.7 variant first detected in the UK; the B.1.351 variant detected in South Africa; the B.188.8.131.52 variant detected in Brazil; and the B.1.671 variant circulating in India.
It remains to be seen whether the mRNA vaccines will be equally effective against a broader range of diseases.
PS: In discussing the COVID-19 pandemic, you have often drawn lessons from HIV/AIDS. You designed the strategy to develop the first treatment for HIV/AIDS. What were the biggest mistakes your approach corrected, and how might that approach be applied to today’s efforts to find an effective COVID-19 treatment?
WAH: Shortly after the discovery that HIV was the agent responsible for AIDS, there was enormous enthusiasm for developing a vaccine. Our early studies showed that people infected with HIV had among the highest B-cell and T-cell immune responses ever recorded, yet infection still progressed to disease and death. Coupled with the observation that vaccines do not prevent primary infection, but serve as a “fire alarm” to create a rapid immune response, it was evident that a full-blown immune response to HIV infection would neither stop the initial infection nor prevent disease.
It took several years for the scientific community to switch its focus from vaccines to antiviral drug therapy. It also took some time to recognize that combination therapies with drugs of very low toxicity would be required to control HIV infections for a lifetime. Only recently have combinations of long-acting antiviral drugs of low toxicity been developed that offer many months or even a year of protection following a single dose. Such prophylactics are different from therapeutics in terms of tolerability. Since prophylactics are taken by fully healthy people, the adverse effects must be very low to nonexistent. Similarities in tolerability and efficacy affect the development of vaccines and prophylactic drug therapies for SARS-CoV-2.
We’ve been much luckier with vaccines for COVID than we ever were for HIV. But we should not take our eye off the ball when it comes to antivirals as a means to curtail significantly the current pandemic. A recently published study suggests we may be getting close to a cocktail of drugs (in this case, a polymerase inhibitor and two hepatitis C drugs) that might be easily produced and distributed – and very effective.
PS: Where do you hope HIV/AIDS research will go next?
WAH: I believe the new targeted immune therapies, coupled with a growing understanding of cellular reservoirs of latent HIV, will permit eradication of the disease from those infected and bring about real cures. I believe this will be made possible by recent advances in engineered T cells that can seek out and destroy very specific cell populations. I am also encouraged by the possibility that single-shot, once-yearly combinations can provide effective prophylaxis.
PS: Your book My Lifelong Fight Against Disease: From Polio and AIDS to COVID-19 is described as an “insider’s account of some of the most brilliant medical breakthroughs in modern history,” which aims to inspire “all readers to appreciate science as a humanistic enterprise.” Why is the humanistic dimension of science so essential?
WAH: At the beginning of my career, I sought to acquire all the tools of science – mathematics, chemistry, physics, biology – required to solve complex disease problems. I am thankful for those before me who dedicated their lives to understanding the deepest secrets of nature.
Many scientists are driven by curiosity alone. My goal – and the goal of many of the people with whom I have worked during my career – was to use such knowledge to improve the health of as many people as possible. The combination of curiosity-driven research and humanistic intent has proved enormously powerful.
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