Does mixing COVID boosters provide better immunity?

Millions of Australians are now eligible for a COVID-19 vaccine booster dose with either Comirnaty (Pfizer) or Spikevax (Moderna).
 
Individuals can choose one or the other, regardless of which vaccine they received for their first two doses, but there are a few exceptions.
 
ATAGI advises only those who are unable to have Pfizer for medical reasons, or who have already had two doses of AstraZeneca, can elect to receive the Vaxzevria (AstraZeneca) vaccine as a booster dose.
 
While the TGA has granted provisional approval for the Pfizer booster in 16–17-year-olds, boosters are not recommended for those under 16 years and there are currently no vaccines approved for use as a booster in this age group.
 
But for the rest of Australians, it’s a mix between personal choice and vaccine availability.
 
Why bother boosting?
We know a primary two-dose course of Astra Zeneca provides almost no protection against symptomatic Omicron infection, with the latest UK data confirming the effectiveness against Omicron drops from 45–50% at 2–4 weeks, to almost 0% at 20 weeks post second dose.
 
The same data, based on PCR test results, shows the effectiveness of two doses of Pfizer or Moderna against the Omicron variant drops from around 65–70% at 2–4 weeks, to around 10% at 20 weeks post second dose.
 
A booster dose of Pfizer or Moderna increases waning protection back to around 65–75% at 2–4 weeks following the third dose, although this drops again to 55–65% at 5–9 weeks, and 45–50% after 10 weeks.
 
Although protection against symptomatic disease appears to wane over time even with a third booster dose, the good news is that protection against hospitalisation remains high.
 
The effectiveness of a third booster dose against hospitalisation with symptomatic disease from the Omicron variant sits around 92% at 2–4 weeks post third dose, with a smaller drop to 83% after 10 weeks.
 
Which booster is best?
Despite predating the widespread circulation of the Omicron variant, new research published in the New England Journal of Medicine has found the antibody response against COVID-19 after a third booster appears to be stronger if the booster is a different vaccine to the one used for the original two-dose primary course.
 
The US-based team tested three boosters, namely Pfizer, Moderna and Johnson & Johnson, the latter of which is not currently used in Australia but is comparable to AstraZeneca.
 
The open-label phase 1/2 trial of 150 individuals found that all combinations boosted neutralising antibodies, but there was a stronger response in those who mixed and matched their vaccines.
 
‘Homologous boosters increased neutralising antibodies by a factor of 4–20, whereas heterologous boosters increased titres by a factor of 6–73,’ write the authors.
 
T cell responses also increased for every group, except those who had the Johnson & Johnson booster.
 
Infectious diseases physician and microbiologist Associate Professor Paul Griffin welcomes the news.
 
‘It adds to the body of evidence that supports what we’ve already suspected for quite a while, which is that so-called mixing and matching of vaccines seems to confer advantages in terms of immune response,’ he told newsGP.
 
Professor Griffin says that the recent approval of Novavax as a primary course vaccine will help expand the potential mix and match options.
 
‘Our ability to swap around vaccines will also be increased once Novavax is approved as a booster,’ he said.

What does other research suggest? 
This latest US data appears to be supported by findings from the UK.
 
Published in The Lancet in December 2021, a randomised controlled phase 2 trial of booster doses in almost 3000 individuals found a similar trend in improved effectiveness of heterologous boosters at four weeks post third dose.
 
In those who received a primary two-dose course of AstraZeneca, the increase in antibody levels (anti-spike IgG) following a third booster compared to controls was three-fold for AstraZeneca, almost nine-fold for Novavax, 25-fold for Pfizer and 32-fold for Moderna.
 
In those who received a primary two-dose course of Pfizer, the increase in antibody levels compared to controls was around five-fold for both AstraZeneca and Novavax, eight-fold for Pfizer and 11-fold for Moderna.
 
Professor Dale Godfrey from the Doherty Institute told newsGP that while the research suggests Moderna might be slightly stronger than the Pfizer vaccine in boosting neutralising antibodies, it is important to remember the Moderna vaccine used in these studies was at the full-strength dose (100μg).
 
While this is the normal strength used for primary vaccination overseas, the Moderna booster currently in use in Australia is half that dose.
 
He also points out that heterologous boosting may have advantages for the T cell response.
 
‘The evidence seems to suggest that you might get a more enriched CD8+ T cell response with heterologous boosting – if the first doses are from adenoviral vector vaccines such as the Ad26 vaccine [Johnson & Johnson] in the NEJM paper and the AstraZeneca vaccine that was widely used in Australia – than homologous boosting,’ Professor Godfrey said.
 
‘Unlike neutralising antibodies, T cell responses are less susceptible to immune evasion. While they won’t necessarily stop you from getting infected, they are likely to be important for preventing severe disease.’
 
As a result, the findings from this and other similar studies suggest patients do not need to match vaccines for an effective booster response.
 
‘Heterologous boosting is fine. There are several studies now that support that it is at least as good as, if not better than, homologous boosting,’ Professor Godfrey said.
 
Associate Professor Paul Griffin agrees.
 
‘The best booster to get is the one that you can get first as soon as you’re eligible,’ he said.
 
‘But if there is an opportunity to swap over to one you haven’t already had, that may confer added benefit.’
 
And with some countries rolling out a fourth booster due to ongoing concerns over waning immunity, it appears heterologous boosting may yet become a more permanent feature of Australia’s fight against the pandemic.
 
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