The race to tame COVID-19 has resulted in a wealth of research, new vaccines and promising treatments that hold out the promise of an end to the pandemic. But many questions remain.
Here, Max Nisen and Sam Fazeli, who cover health care and the pharmaceutical industry for Bloomberg Opinion and Bloomberg Intelligence, discuss some of the most pressing ones. The dialog has been edited and condensed.
MN: Do we really need a booster or third shot? What exactly should we expect them to do?
SF: Fortunately, the vaccines that have been studied most – those from AstraZeneca Plc, Pfizer Inc.-BioNTech SE and Moderna Inc. – continue to provide high protection against severe disease or hospitalization for at least six months after two doses. From that perspective, we do not need a third shot. But we are seeing a meaningful drop in the protection against infection. This is expected, given that vaccine-induced antibodies decline with time, and that we’re now grappling with the more contagious delta variant. The real question is whether the protection against severe disease will also start to wane. I think we will see data from Israel on this, as well as from the U.S. Food and Drug Administration at its Sept. 17 meeting. Waning immunity against severe disease could happen if the vaccine always needed a third shot, which wasn’t studied because initial vaccine trials focused on speed. Several highly effective existing vaccines require third shots to generate stronger protection. But because leading COVID-19 vaccines use newer technologies, we don’t really know the best way to dose. It’s possible that third shots may need to be viewed as standard for COVID-19 vaccines, rather than a luxury. Either way, it’s critical that we not oversell the potential benefits of a third shot. Antibody levels will wane again and the risk of infection may rise, but the risk of severe disease and from future variants should be lower.
MN: How long should we wait to boost, and does it vary by vaccine or population?
SF: The only way to truly answer this question is with big studies. But we don’t have time to do that. Even mild infections in the vaccinated may become more troublesome this winter when combined with another respiratory virus such as the flu or respiratory syncytial virus (RSV). We should certainly consider third shots in at-risk people to prevent that. But the definition of at-risk is rather arbitrary. Who is a front-line worker, what is the right age cutoff for an older person and what constitutes immunocompromised when it comes to the coronavirus and these vaccines? Should someone who finished cancer therapy four weeks ago get a third shot, or is it two weeks? I think it may be much easier – if you set aside supply and global equity issues – to just give a third shot at six or eight months to everyone over a certain age.
MN: As of now, vaccines have been approved only for those 12 and older. What are the risks to young children, especially as schools reopen, and when will shots be approved for them, assuming they will eventually need them?
SF: Children are often thought of as being at very low risk from COVID, but this is not exactly correct. A lot of our data is based on a period that involved home schooling as well as social distancing and mask-wearing. We are now going into a very different setup, with mask mandates a major point of contention just as the more infectious delta variant is dominating the scene. Also, most children are back at school, with many facilities not having updated their ventilation systems. The risk of long-term symptoms are real for children, and the number of kids in the hospital with COVID is increasing. On top of all this, we don't know what happens to a child infected with both COVID and one of the other respiratory diseases to which they have lower immunity than usual because of social distancing, such as flu and RSV. For all these reasons, it would be good to have vaccines available for children, but there needs to be a good deal of safety data before regulators will approve them. It’s a tough situation, but it’s important to get it right.
MN: What do antibody levels actually mean for vaccine efficacy and the risk of reinfection? Is it just antibodies that matter?
SF: Again, it comes down to definitions. Recent studies suggest antibody levels correlate to protection against infection. What we need to know is how to measure protection against severe disease or hospitalization. Antibodies are clearly important, but so is the other, “cellular” arm of the immune system. This involves “T-cells” trained to find and kill infected cells, limiting the spread of the infection within the body. This part of the equation has proved harder to study; severe cases rarely occurred in the late-stage, phase III trials, and T-cells are harder to measure.
MN: Are there any safety concerns with boosters? Does that influence which ones we should be using, and what about dosing?
SF: We don’t know for sure. Remember first that most, if not all, vaccine-induced side effects appear within the first two months of immunization, which is exactly what has happened with COVID-19 vaccines. We know that there is a risk of rare blood clots with the AstraZeneca and Johnson & Johnson vaccines among those younger than 40 or 50, but only after the first dose, so a third shot of these vaccines in those who already had two should be OK. However, these shots use a viral vector that the immune system may come to recognize, potentially making a third shot less effective. With the mRNA vaccines from Pfizer-BioNTech and Moderna, there’s a risk of heart inflammation in younger individuals after the second shot, which may increase after a third. Mixing vaccines may provide a more effective boost, but may also introduce or heighten the above uncommon risks. Clinical trials happening now will provide more information, but they may not tell us much about rare side effects. As for dosing, data from the U.K., which is one of two countries along with Canada that have systematically used a longer dosing period between the first and the second shot, suggests that the protection afforded by this schedule was at least as good if not better. We still don’t know whether the immunity will wane at a slower pace. U.K. data doesn’t address this yet; we need more time to get a better picture.
MN: Might Moderna's vaccine be more effective or durable than Pfizer-BioNTech’s, as some studies suggest?
SF: It may be. The Moderna vaccine uses more than three times the amount of the mRNA that prompts the body to make the spike protein of the coronavirus and generate an immune response than Pfizer-BioNTech’s. So it is not surprising that you get more antibodies to start with. And assuming the antibodies generated by the two vaccines are the same from a qualitative perspective and decline at the same rate, then you would expect levels in people vaccinated with the Pfizer-BioNTech shot to fall below the threshold for protection sooner. But let’s not forget, we are talking about prevention of infection and mild disease here. There is no solid data that suggests protection against severe disease is substantially different between these two vaccines, or indeed with the AstraZeneca shot.
MN: What accounts for the huge differences in estimates of vaccine efficacy around the world?
SF: Oh many things. First, not everyone is measuring the same things. Some look at all infections, others symptomatic disease. Countries use different PCR tests and have different rules for testing. There are also differences in demographics, like age and health status, as well in the type of vaccine used and dosing schedules. And then there is varying timing of vaccination rollouts between countries and within them based on age or other factors. There are certainly other explanations as well.
MN: Will we need a fourth shot? Will it have to be tailored to specific variants?
SF: It’s possible, but from what I understand about the science, it’s not likely unless we continue to worry about even mild infection levels as is the case right now. There is a chance that a third shot after six or eight months pushes the immune response to the point where it is better at fighting both existing and future variants, though this has to be studied more. Current data suggests that boosting with existing vaccines develops strong antibodies against even evasive variants. But if a really troublesome variant arises, we could need another shot that specifically targets it.
MN: How much should we worry about new mutants that are more deadly or evade vaccine efficacy? How can we avoid them?
SF: You have to bear in mind that it’s not just the virus that evolves. As I said earlier, even without a third shot, the immune system matures over time. Normally, the more it sees an offending pathogen, the better it gets at responding to it. Like the viruses they help fight, the “B-cells” that produce antibodies can mutate their genes. We don’t know whether the virus will become more or less deadly over time, however. The common coronaviruses that cause colds may have started as more serious diseases. Recent research suggests that there would need to be 20 mutations in the “spike” protein to make the virus that causes COVID-19 completely evade antibodies from vaccinated people or those previously infected. But they also showed that people who had been vaccinated after an infection had antibodies that neutralize even this super-mutant virus. Data also shows that the virus mutates less in those who are fully vaccinated, so the risk of variant development will fall over time. And lastly, the T-cell part of the immune response chases different virus targets and won’t be affected by mutations that help the virus escape antibodies.
MN: Have we learned any more about long COVID, and what's the risk on that front for the vaccinated?
SF: Yes, it’s being studied. Recent data found a 50% reduction in the risk of long COVID symptoms for vaccinated people. That leaves another group that does have symptoms, but we need more data to know how serious they are. Self-reported symptoms can also be very error-prone. A recent study found that 66.5% of children who tested positive for COVID reported symptoms after three months. That sounds pretty bad – until you see that 53.3% of those who tested negative also reported lasting symptoms. It’s important to be careful with these sorts of analyses.
MN: Are any new COVID treatments coming? Can they make a real difference?
SF: Yes and yes; we already have highly effective monoclonal antibody therapies that significantly reduce the risk of developing severe disease in infected people, even those with a compromised immune system. Some of these therapies can be used as prophylactic treatment in vulnerable individuals. We can also look forward to data for more convenient oral antiviral drugs from Merck and Ridgeback Biotherapeutics, Pfizer and a collaboration between Roche Holding AG and Atea Pharmaceuticals Inc. that could also curb disease. Final-stage trial data is expected by the end of the year.
MN: When will the pandemic be over?
SF: At this point, it's hard to avoid thinking that COVID will be an endemic virus like those that cause the common cold or flu — it will circulate for years to come, but with less of an impact in the future. The end of the acute pandemic phase will come when vaccine and infection-driven immunity get to a point where the risk of bad outcomes is relatively low and we can stop focusing on case counts globally. You'll still need surveillance, have small outbreaks and may need continued vaccination in some groups, but I think most COVID-related restrictions will sunset within a year or so. The big swing factors that will determine whether the effective end comes faster or slower are any further mutations and the speed with which vaccine supply is directed toward the developing world, where inoculation rates are lagging. An effective oral antiviral that can quickly treat the infected would also bring a quicker end to the pandemic phase.
Sam Fazeli is senior pharmaceuticals analyst for Bloomberg Intelligence and director of research for EMEA.
Max Nisen is a Bloomberg Opinion columnist covering biotech, pharma and health care. He previously wrote about management and corporate strategy for Quartz and Business Insider.
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