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. 

AstraZeneca + Pfizer vaccines = Better immunity omicron

After reports of side effects in certain populations with the AstraZeneca vaccine, the UK and much of Europe decided to use Pfizer injections as a second injection in certain age groups, creating an experience of mixed natural dosage. New data from the UK suggests that this particular mix offered additional immunity against the omicron variant compared to those with other platforms.

In many ways, this is not surprising. Researchers have known for years that mixing and matching vaccines can produce stronger or longer lasting immunity and also provide better defense against variants. What they didn’t know was how mixing different vaccine platforms would affect immunity against SARS-CoV-2 and serious illness.

Given the latest scientific data, we should devote much more effort to studying these effects. Below, Therese speaks with Bloomberg Intelligence Senior Pharmaceutical Analyst Sam Fazeli about the new mixed-dosing data.

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 emerged in South Africa last November and has started to spread.

Sam Fazeli: A new study of vaccinated people in the UK, by Zijun Wang and colleagues, showed that an injection of Pfizer-BioNTech’s Comirnaty vaccine after a first dose of Astra Zeneca‘s Vaxzevria induced an immune response that not only beat two shots of the Astra vaccine, but was even better than two doses of Pfizer. This was particularly the case when the authors examined neutralizing antibody (NAb) levels against BA.1, the original omicron variant of concern.

TR: What difference are we talking about? And does that mean stronger immunity or immunity that lasts longer, or both?

SF: Levels of neutralizing antibodies in the mixed vaccinated group one month after the second injection were 10 times higher than for two injections of the Pfizer vaccine (mRNA), one third of the individuals in this latter group having no neutralization. This means that those who received a mixed vaccine would probably not only be better protected against an infection, but also, given the higher level of antibodies, this protection could last longer.

TR: The study also looked at why having two Pfizer injections might be disadvantageous when it comes to omicron. Can you explain?

SF: The study showed that six months after being vaccinated with two injections of the same mRNA vaccine (Pfizer), people had higher levels of memory B cells (cells that turn into antibody-producing cells when new infection occurs) specific to the receptor binding domain (RBD) of the virus spike protein than those who received a mixed vaccination.

The RBD of the spike protein is the part that 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 in this region that most of the mutations of the virus occur to circumvent our protective antibodies.

So if most of your memory B cells target this region, an infection may take longer to resolve or be more likely to lead to more severe disease because the virus mutates the RBD and evades antibodies. In the mix-and-match group, there were more non-RBD antibodies.

TR: What about the T-cell response, since these are immune cells that limit the severity of disease and contribute to longer-lasting immunity. How does a mixed vaccination regimen compare on this front?

SF: Here we have two studies that support the notion of using mixed vaccines. Zoltan Banki and colleagues showed that levels of inflammatory markers (cytokines) that mediate the T-cell immune response were higher in those who received a mixed vaccination compared to mRNA-only injections. The authors also showed that there were more multifunctional T cells after mixed vaccination. Higher multifunctionality and higher cytokine levels suggest that protection after mixed vaccination may be better than after two injections of the same vaccine.

TR: In order to deliver more first vaccines quickly despite supply limitations, the UK has opted for a 12-week gap between the first and second vaccines, much longer than other countries. Could this have had an impact on the results?

SF: Yes, the difference between a mixed vaccination and two injections of Pfizer could be due to the use of two different vaccines and/or this longer gap between the first and the second injection in people vaccinated with AstraZeneca followed by Pfizer , as opposed to just one month apart for two Pfizer injections.

TR: We are currently seeing a fifth wave of the virus in South Africa, which has mixed the Johnson & Johnson vaccine (similar to that of AstraZeneca) with that of Pfizer. However, the vaccination rate in South Africa is still very low (only 32% fully vaccinated and only 5.4% vaccinated). Can we learn anything from this experience?

SF: In fact, there was a study (also by Zhang et al.) that looked at the immune response to mRNA vaccines and injections from J&J and Novavax, showing that only those who received an injection of the J&J vaccine, which is similar to the downed Astra in that it uses an adenoviral vector, produced a specific type of memory B-cell that is found to be important for mucosal immunity (immunity in the nasal passages and surfaces of the lungs as opposed to “humoral” immunity which is blood based) in two animal models. Mucosal immunity was not demonstrated after mRNA vaccines, suggesting potentially higher protection against reinfection in those who received the J&J vaccine before or after an mRNA vaccine.

But it’s clear that for any of these vaccines to be effective, people need to take them and get their booster shots. What we do know about the last South African wave is that it was short lived and had even lower infection morbidity/mortality than the omicron BA.1 wave.

TR: There’s no guarantee that we won’t get a new variant with different properties at some point. Can we learn broader lessons about vaccinations from the new data?

SF: Continued injections with the same vaccine only provide short-term protection and may not be necessary given the very robust protection against severe disease in most people with the third vaccine, even during the omicron wave . In fact, one of our recent analyzes showed that ICU admission rates per case in the United States, which has the BA.2.12.1 subvariant, are the lowest on record.

What we really need to do is see if using a different vaccine platform would give us longer and better immunity than repeatedly going for mRNA injections.

TR: Does the mix of vaccine platforms matter when it comes to severe illness and hospitalizations or is the difference only in terms of the likelihood of infection? And isn’t the problem of side effects with Astra and J&J shots always a problem?

SF: The answer to the first part of the question is that we just don’t know. More studies are needed to determine whether or not those who received mixed doses have better protection against serious diseases. For this you need a very large cohort since the difference, if any, may be small.

The side effect issues with the two adenoviral vaccines are much better understood and there are even proposed modifications that can reduce them significantly. But for this to be investigated, government-funded institutions may need to get involved because manufacturers have essentially stopped investing in them.

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

Therese Raphael is a columnist for Bloomberg Opinion covering health care and British politics. Previously, she was the editorial page editor of The Wall Street Journal Europe.

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

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