Could the UK inadvertently have given some of its population the best immunity possible against SARS-CoV-2?
In many ways, that’s not surprising. Researchers have known for years that mixing and matching vaccines can produce stronger or longer-lasting immunity and also provide a greater defense against variants. What they didn’t know was how mixing the various vaccine platforms would affect immunity to SARS-CoV-2 and serious disease.
Given the latest scientific data, we should spend a lot more effort studying such effects. Below, Therese speaks with Bloomberg Intelligence senior pharmaceutical analyst Sam Fazeli about the new data on mix-and-match dosing.
Therese Raphael: How has the particular combination prevalent in the UK potentially given people an immune advantage when it comes to the omicron BA.1 variant that first appeared in South Africa last November and began spreading.
Sam Fazeli: A new study looking at vaccinated individuals in the UK, by Zijun Wang and colleagues, showed that a shot of Pfizer-BioNTech’s Comirnaty vaccine following a first dose of AstraZeneca’s Vaxzevria induced an immune response that not only beat two shots of the Astra vaccine, but looked even better than two doses of Pfizer. This was especially the case when the authors looked at neutralizing antibody (NAb) levels against BA.1, the original omicron variant of concern.
TR: How big a difference are we talking about? And does that mean stronger immunity or immunity that lasts longer, or both?
SF: Neutralizing antibody levels in the mixed vaccine group one month after the second shot were 10 times higher than for two shots of the Pfizer (mRNA) shot, with a third of individuals in this latter group having no neutralization at all. This means that those who had received a mix-and-match vaccine would likely not only be better protected against an infection, but also, given the higher level of antibodies, this protection may last longer.
TR: The study also went into why having two shots of Pfizer might be disadvantageous when it comes to omicron. Can you explain?
SF: The study showed that six months after being vaccinated with two shots of the same mRNA vaccine (Pfizer), people had higher levels of memory B-cells (cells that convert to antibody-making cells when a new infection occurs) specific to the receptor binding domain (RBD) of the virus’s spike protein than those who had a mix-and-match vaccination.
The RBD of the spike protein is the part which first engages with a human cell and “binds” to its receptor, the human ACE-2 molecule. Without this binding, no infection would occur. Antibodies that interfere with this binding “neutralize” the virus. It is therefore this region where most of the mutations occur in the virus to get around our protective antibodies.
So if most of your memory B-cells target this region, an infection may take longer to resolve or have a higher chance to lead to more severe disease because the virus mutates the RBD and escapes the antibodies. In the mix-and-match group, there were more non-RBD antibodies.
TR: What about the T-cell response, since those are immune cells that limit disease severity and contribute to longer-lasting immunity. How does a mixed vaccine regime compare on that front?
SF: Here we have two studies that support the notion of using mix-and-match vaccines. Zoltan Banki and colleagues showed that the levels of inflammatory markers (cytokines) that mediate the T-cell immune reaction was higher in those who received a mixed vaccination compared with just mRNA shots. The authors also showed that there were more multifunctional T-cells after mixed vaccination. Higher multifunctionality and higher levels of cytokines suggest the protection after a mixed vaccination may be better than after two shots of the same vaccine.
TR: In order to deliver more first shots quickly amid supply limitations, the UK opted for a 12-week gap between the first and second vaccine shot, much longer than other countries. Could that have impacted the findings?
SF: Yes, the difference between a mixed vaccination and two shots of Pfizer could be due to the use of two different vaccines and/or that longer gap between the first and second shots in those vaccinated with AstraZeneca followed by Pfizer as opposed to only a one-month gap for two shots of Pfizer.
TR: We are now seeing a fifth wave of the virus in South Africa, which mixed the Johnson & Johnson vaccine (similar to AstraZeneca’s) with Pfizer’s. However, South Africa’s vaccination rate is still very low (only 32% fully vaccinated and only 5.4% boosted). Can we learn anything from that experience?
SF: Actually, there was a study (also by Zhang et al.) which looked at the immune response to mRNA vaccines and the shots from J&J and Novavax, showing that only those who received a shot of the J&J vaccine, which is similar to the Astra shot in that it uses an adenoviral vector, produced a specific type of memory B-cell that’s found to be important for mucosal immunity (immunity in the nasal passages and the surfaces of the lungs as opposed to “humoral” immunity which is blood based) in two animal models. Mucosal immunity has not been shown following mRNA vaccines, suggesting a potentially higher protection against reinfection in those who received the J&J shot before or after an mRNA vaccine.
But clearly for any of these shots to be effective, people need to take them and get their boosters. What we do know about the latest South African wave is that it was short-lived and had even lower morbidity/mortality per infection than the omicron BA.1 wave.
TR: There is no guarantee we won’t at some point get a new variant with different properties. Can we draw any broader lessons on vaccinations going forward from the new data?
SF: Continued shots with the same vaccine only gives short term protection and may not be needed given the very robust protection against severe disease in most people with the third shot, even during the omicron wave. In fact, one of our recent analyses showed that the rates of ICU admission per case in the US, which has the BA.2.12.1 subvariant, is the lowest it has ever been.
What we really need to do is look at whether using a different vaccine platform would give us longer and better immunity than repeatedly going to mRNA shots.
TR: Does the mixing of vaccine platforms matter when it comes to severe disease and hospitalization or is the difference just in terms of likelihood of infection? And isn’t the side effect issue with the Astra and J&J shots still a problem?
SF: The answer to the first part of the question is that we just don’t know. More studies are required to tease out whether those who had mix-and-match doses have better protection against severe disease or not. For this, you need a very large cohort given that the difference, if any, may be small.
The side effect issues with both the adenoviral vaccines are much better understood and there are even proposed modifications that may reduce them significantly. But for this to be studied, government-funded institutions may need to get involved as the manufacturers have essentially stopped investing in them.
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 covering health care and British politics. Previously, 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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