A Fourth Shot Against Omicron? Don’t Count It Out

(Bloomberg Opinion) -- “No one should be in any doubt: There is a tidal wave of omicron coming, and I’m afraid it is now clear that two doses of vaccine are simply not enough,” Boris Johnson said in a statement Sunday night. The Prime Minister’s warning tallies with modeling by researchers at the London School of Hygiene and Tropical Medicine predicts between around 25,000 and 75,000 deaths from the new variant this winter in Britain. On Sunday, Johnson announced a plan to super-charge the country’s booster program so that everyone over 18 will be offered a third shot before the end of the year.

Given the current pace of roll-out, that will take some doing. But the question many have been asking — apart from whether another Christmas will be ruined by Covid — is how potent booster shots will be against the new variant.

One U.K. study published last week suggests booster shots provide 70% to 75% protection (depending on whether the initial doses were from AstraZeneca or Pfizer) against symptomatic disease from omicron. But Pfizer CEO Albert Bourla said last week that a fourth vaccine dose could be needed, perhaps sooner rather than later. Bloomberg Opinion’s Therese Raphael talks to Bloomberg Intelligence senior pharmaceutical analyst Sam Fazeli about how booster shots are likely to match up against the omicron variant. 

Therese Raphael: The evidence is clear that a third vaccine shot dramatically increases our protection against serious illness from Covid-19. Is it premature to begin thinking about a fourth dose?

Sam Fazeli:  It isn’t premature if data suggest that a variant-specific vaccine — that is, a vaccine that has been adapted specifically to address the mutations in the omicron variant — will give better protection.

There was an interesting little snippet in the BioNTech presentation last week showing that blood from people who received a third shot of a vaccine representing the spike protein of the alpha variant had more than four times higher levels of neutralizing antibodies compared with those who got a booster with the current vaccine — which is what everyone is using. Given that the alpha variant shares some key mutations with omicron, this may suggest an omicron-directed vaccine could also do a lot better.

But the question is whether current boosters are good enough to continue to suppress the risk of severe disease, driven by cellular immunity, as they are expected to be. So would we need a fourth shot if omicron infections don’t translate into a high burden on healthcare services, as appears to be the case in South Africa so far (though I caution that extrapolating from data from South Africa to other countries is risky given the very different demographics there)?

TR: Some of us have only just had our booster shots and of course most people still haven’t had a third shot. What should the timing for a fourth shot be if indeed a variant-specific dose is required? Originally, Bourla said he thought a 12-month gap would be fine; now he's saying it might have to be much sooner after a third shot.

SF: So that’s what we don’t know. Some early data from Israel suggests that the effect of boosters on reducing infection risk is already being lost barely six months after the campaign started. I stress that these are early data and a lot more time and analysis is needed to have a complete picture.

But I think we need to be very clear about what it is we are trying to achieve. If countries continue to target infections as the main metric for managing the pandemic, there may be a need for regular boosters. The principle is the same as after the second shot, in that antibody levels which protect against an infection fall over time, even if potentially at a slower pace. By that metric, even if the virus doesn’t throw us another curve ball with a new variant, we will need to revaccinate regularly.

TR: That would prove a nice little annuity for the vaccine-makers, but a challenge for public health systems. Do you see this becoming like the flu vaccine, where new formulations are devised annually?

SF: A lot depends on how much the virus changes going forward, and to be honest that’s anyone’s guess. The original expectation that SARS-CoV-2 would not mutate so fast has turned out to be not quite right. Then we have to recognise the fact that the virus is establishing a kind of equilibrium with its hosts (humans and also some animals), and it’s very possible that the ancestral virus, which started the pandemic, was no where near its peak fitness. And then we have the hosts’ immune response evolving, putting new pressure on the virus to change. Until this comes to a natural equilibrium — as we have with other coronaviruses, where most infections are mild — we may need vaccine updates. 

TR: Are there any dangers we should be aware of in administering the same vaccines repeatedly — either to those receiving them or how the virus might change in response?

SF: Yes. The immune system is very complex and we should not assume anything until there is data to prove it. There is a risk that a vaccine that is not sufficiently different from a previous one simply stimulates the immune system to make more of the same antibodies, rather than new ones. There was a hint of this in some data from Moderna which showed a slightly lower neutralization of the beta variant in blood from people who received a third shot of a beta variant vaccine than those who simply received the current vaccine as a third shot.

TR: Obviously from a public health perspective, the forever booster becomes a challenge. Even if supply is not an issue, we might see more demand problems and stress on health systems in having to distribute so many doses. And then there's the question of vaccine equity and getting these additional doses to poorer countries. What are the chances that Covid-19 eventually become a mild disease and these efforts become unnecessary?

SF: I think this is what everyone is hoping, based on the early data coming out of South Africa. Whether it’s omicron that gets us there or a future variant, is not known. But eventually the hope is that repeated infections, especially for those who have been vaccinated, results in a milder disease. Then what we need is to be able to identify those who are at risk of developing severe disease, and protect them better. Remember that vaccines are not going to be our only weapon. We have antiviral drugs that can really help manage the situation.

More From Writers at Bloomberg Opinion:

• Omicron Questions We Will Keep Asking Through the Holidays: Bobby Ghosh, Therese Raphael and Sam Fazeli
• Omicron Scrambles What We Know About Immunity. Now What?: Faye Flam
• Revenge Christmas Is Coming. With or Without Omicron: Andrea Felsted

This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.

Therese Raphael is a columnist for Bloomberg Opinion. She was editorial page editor of the Wall Street Journal Europe.

Sam Fazeli is senior pharmaceuticals analyst for Bloomberg Intelligence and director of research for EMEA.

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