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Covid-19 vaccine mixing: could heterologous boosters improve immunity?

As the world grappled with vaccinating against Covid-19 last year, a mix-and-match approach to jabs emerged as a potential solution to roadblocks like vaccine hesitancy, safety concerns, and supply chain issues.

In the months since, numerous studies have shown that administering different Covid-19 vaccines for the first and second doses induces a strong immune response against the novel coronavirus, and recent research has even suggested that mixing jabs is more effective than administering two doses of the same vaccine.

Now, with vaccine booster programmes underway across the globe, the next question is whether this mix-and-match rule applies to booster doses. More than 36 million booster doses have been administered in the UK so far, while over 62 million people in the US have received a third shot. According to GlobalData’s Covid-19 booster dashboard, millions of people in the US have received heterologous booster shots – that is, the third vaccine dose differs from the ones given as primary doses.

While most people who were given Pfizer-BioNTech or Moderna jabs for their initial vaccination received the same vaccine as a booster, the majority of those who first received Johnson & Johnson’s (J&J) one-shot jab were given a different brand as a booster dose. Around 41% of J&J recipients received the Moderna vaccine Spikevax as a booster, while roughly 32% were given the Pfizer-BioNTech Comirnaty jab for their third dose.

So, the mixed vaccine approach has been adopted for booster shot programmes – but which primary vaccine-booster combinations, if any, offer the best protection against Covid-19?

The science so far

Research into heterologous boosting is in the early stages, but a number of studies have indicated that mixing certain vaccines could result in better immunity against Covid-19.

Results from the UK Cov-Boost study, published in The Lancet in December, showed that six different Covid-19 vaccines are safe and provoke strong immune responses when given as boosters after two doses of either AstraZeneca or Pfizer-BioNTech. Seven vaccines were studied in the trial: the Oxford-AstraZeneca, Pfizer-BioNTech, Novavax, J&J, Moderna, Valneva, and Curevac jabs.

The randomised Phase II trial revealed that while all the vaccines were safe to use as third doses, immune responses varied widely among the different shots used. All seven jabs boosted spike protein immunogenicity when given after two doses of the AstraZeneca (AZ) vaccine, while all except the one by Valneva, did so after two shots of the Pfizer-BioNTech jab.

The Cov-Boost researchers also found that the Spikevax and a Comirnaty jabs generated the highest antibody levels, suggesting that mRNA vaccines may have the edge when it comes to the most effective booster doses.

Additionally, a small US study conducted last year – which is yet to be peer-reviewed – assessed all nine possible primary and third dose combinations of the three Covid-19 jabs available in the US. According to the study preprint, every combination increased neutralising activity against the virus – but using an mRNA vaccine (either Pfizer-BioNTech or Moderna) as a booster appeared to induce a stronger antibody response than using the J&J shot.

This doesn’t mean J&J’s jab isn’t a valuable weapon in our anti-Covid armoury. Early data from an independent study by the US Beth Israel Deaconess Medical Center has suggested that heterologous boosting with the J&J vaccine offers good protection against SARS-CoV-2. The study results, which have not yet been peer-reviewed, showed that a J&J booster given six months after a two-dose primary vaccination with Comirnaty increased both antibody and T-cell responses.

The study authors also noted a greater increase of CD8+ T-cell responses after the J&J shot, compared with the Pfizer-BioNTech jab.

Evidence supporting AZ’s vaccine as a booster, regardless of the primary vaccines used, is also growing. New data from an ongoing trial has shown that an AZ booster dose increased the immune response to Beta, Delta, Alpha and Gamma variants in those previously vaccinated with either the AZ jab or the mRNA vaccines.

A trial preprint recently published in The Lancet also found that a third dose of AZ following primary vaccination with Sinovac’s CoronaVac jab significantly increased antibody levels. The study also found that binding and neutralising antibody levels rose after third doses of the Pfizer-BioNTech, J&J and Sinovac vaccines.

While  various early-stage studies of heterologous boosters point to different vaccine brands as the most effective, one thing the research has conclusively shown is that Covid-19 booster shots work. Regardless of the kind of jab administered, the evidence indicates that a third coronavirus vaccine significantly boosts the body’s immune response against the virus – and that boosters are therefore a valuable defence against the continued threat of SARS-CoV-2 and its variants.

Heterologous boosters: regulators’ stances

The US Food and Drug Administration approved heterologous booster shots in October, and the country’s Centers for Disease Control and Prevention (CDC) recently reduced the interval between primary and booster jabs from six to five months for those who originally received Pfizer-BioNTech or Moderna vaccines. People who were given the J&J jab as their primary vaccine have been advised to get a booster shot after at least two months.

The CDC has made it clear that Comirnaty and Spikevax vaccines are the preferred option for boosters, due to the risk of serious adverse events associated with the J&J shot. While the mRNA jabs are recommended, the CDC said, a J&J booster may be considered for those who have had a reaction or an allergy to the mRNA vaccines, cannot access an mRNA booster, or wish to get the J&J shot despite the safety concerns.

After analysing the available evidence, the European Medicines Agency (EMA) last month said heterologous boosting “appears as good as or better in terms of immune responses than a homologous booster”. The regulator has recommended that a mix-and-match strategy be considered for booster vaccinations to alleviate issues associated with vaccine acceptance, supply, and availability.

In September last year, the UK drugs regulator MHRA approved the Pfizer-BioNTech, AZ and Moderna vaccines as boosters – but the Joint Committee on Vaccination and Immunisation (JCVI) has advised a preference for either Comirnaty or half of a Spikevax dose to be used for booster vaccinations. The AZ vaccine may be considered as a booster in situations where the mRNA jabs cannot be offered, the JCVI said.

Still, as booster use gets underway, with Israel even administering fourth shots, vaccine equity remains a major issue  – only 9.4% of people in low-income countries have received at least one dose of a Covid-19 vaccine, according to Our World in Data.

World Health Organization head Dr Tedros Adhanom Ghebreyesus has warned against blanket booster programmes, saying there will be enough vaccines to inoculate the global adult population against Covid-19 if wealthy countries do not hoard doses.

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