First U.S. ‘Mix and Match’ COVID Booster Data Are In

A so-called “mix and match” COVID vaccine series using a different booster than the primary series was safe and produced an increase in immune response comparable to or greater than when the primary series and booster were the same vaccine, researchers found.

Adults who were vaccinated with Pfizer, Moderna or Johnson & Johnson vaccines produced an increase in serum binding antibody levels following a booster dose of a different vaccine, with a 4.6-fold to 56-fold increase in geometric mean titers (GMT) at day 15, reported Robert Atmar, MD, of Baylor College of Medicine in Houston, and colleagues.

Moreover, the greatest increase in immune response was among those who had a Johnson & Johnson one-dose primary series, followed by a Pfizer or Moderna booster, with a 33-fold and 56-fold increase, the authors wrote in a highly anticipated preprint on medRxiv, which has not undergone peer-review.

However, they noted that the study was not designed to “to directly compare responses between different booster regimens,” with the sample size being insufficient and the demographics of the group not representative of the U.S. population.

Peter Hotez, MD, PhD, also of Baylor, but who was not involved with the research, tweeted that some are now dismissing Johnson & Johnson homologous booster shots, which are slated for discussion by an FDA advisory committee on Friday.

“Important not to get too carried away with the findings … we should remember the phase 1-2 data on two-dose J&J vaccine was very impressive and could vary based on interval,” he said.

Heterologous boosters have been a hot discussion topic, with the National Institute of Allergy and Infectious Diseases teasing the results of this study at a CDC Advisory Committee on Immunization Practices (ACIP) meeting in September. Federal agencies have not formally advised on “mixing” different vaccine regimens due to lack of data. For example, Pfizer’s COVID-19 booster was only authorized for those who received the Pfizer primary series.

“Heterologous prime boost strategies may offer immunological advantages to optimize the breadth and longevity of protection achieved with currently available vaccines,” Atmar’s group wrote. “if similarly tolerable and immunogenic, [they] could also simplify the logistics of administering booster vaccines.”

The group conducted a phase I/II trial at 10 clinical sites where healthy adults who were fully vaccinated with the Pfizer, Moderna or Johnson & Johnson vaccine at least 12 weeks earlier were divided into nine different groups to receive either a homologous or heterologous booster dose.

Blood was collected for immunogenicity assessments on days 1 (pre-vaccination), 15, and 29, the authors said, and participants recorded adverse events (AEs) for 7 days after vaccination.

Overall, 458 adults were enrolled. They had a mean age of around 50-55, though they were as young as 19 years old. About 80-95% were white.

They found that baseline serum binding antibodies were three-fold to 15-fold lower for those who received the Johnson & Johnson vaccine versus Pfizer or Moderna’s. In addition, 96-100% of participants experienced at least a two-fold increase in serum binding antibodies following a booster with Pfizer or Moderna.

Examining neutralizing antibodies, all sera from Moderna participants had pre-booster neutralizing activity to the reference strain, the authors noted, while 16% of Johnson & Johnson participants and 3% of Pfizer participants had no detectable neutralizing activity.

“Serum neutralization … levels prior to booster vaccination were approximately three-fold and ten-fold lower” for Pfizer and Johnson & Johnson recipients, respectively, the authors noted.

When examining immunogenicity against the Delta variant, they said it was about three-fold to five-fold lower compared to the reference strain following the booster dose, and was similar across vaccines.

In terms of safety, two serious AEs were reported: acute renal failure and acute cholecystitis, neither of which was judged to be related to the vaccine. One severe AE was deemed related to the booster: vomiting leading to a medically attenuated visit the day after vaccination in the Johnson & Johnson group.

Overall, 16% of Moderna boost, 12% of Johnson & Johnson boost, and 14% of Pfizer boost recipients reported vaccine-related AEs. Most were grade 2 or lower, with four grade 3 AEs: one case of vomiting in the Moderna and Johnson & Johnson group, and one each of fatigue and insomnia in the Johnson & Johnson group.

The most common systemic AEs were malaise, myalgia, and headaches, likely to occur 1-3 days after receiving a booster.