12 of today's most pressing COVID questions answered

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 dialogue 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, Pfizer-BioNTech and Moderna — 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?

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?

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?

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 and Atea Pharmaceuticals that could also curb disease. Final-stage trial data is expected by the end of the year.

MN: When will the pandemic be over?