Mixed or Matched Booster Enhances Vaccination Against COVID-19

A booster vaccination increases protection against COVID-19 whether homologous or heterologous with the primary vaccine.


A vaccination booster dose enhances protection against COVID-19 whether it is the same, or differs from the vaccine used in the primary series, according to recently reported results from the MixNMatch phase 1-2, multi-site, open-label clinical trial.

"The actual goal of the study was to determine whether boosting could be performed with vaccines different than those used for the primary immunization," lead author Robert Atmar, MD, Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, told Contagion.

"Because of potential challenges with access to specific vaccine products at different times, the ability to boost with whatever product is available simplifies the delivery of booster vaccines," Atmar explained.

Atmar and colleagues enrolled 458 adults who had completed a COVID-19 primary vaccine regimen at least 12 weeks prior, and had not reported history of SARS-CoV-2 or received a monoclonal antibody infusion.There were approximately an equal number in two age strata (28 to 55 years and ≥56 years).The investigators indicated that they had not laboratory screened participants for exposure to SARS- CoV-2, in order to facilitate rapid enrollment in the trial.

Enrollment continued until approximately 50 persons were in each of the 9 groups to receive a different combination of primary and booster vaccines.The mRNA-1273 (Moderna) was received by 154 participants; the BNT162b2 mRNA (Pfizer) by 153; and 150 received the Ad26.COV2.S (J&J/Janssen).

Immunogenicity assessments were performed on blood samples drawn at baseline, the day before booster dose, and on days 15 and 29 after the booster. These included serum binding antibody levels against the spike (S) protein with proline modification (S-2P); as well as SARS-CoV-2 S-specific CD4+ and CD8+ T-cell responses.Data were collected on adverse events, both local and systemic, for 7 days; and monitoring for unsolicited adverse events continued though 28 days after vaccination.

The investigators reported that all combinations increased antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus, by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55.Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20; and heterologous boosters increased titers by a factor of 6 to 73.There were 2 serious adverse events during the trial, but both were deemed unrelated to the vaccination.

In the assessment of cellular memory, the spike-specfic T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup.CD8+ T-cell levers were more durable, however, in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine was reported to substantially increase spike-specific CD8+ T cells in the mRNA vaccine recipients.

"Our study was designed to determine which approach is most valuable--all led to increased antibody responses," Atmar noted. "The titers achieved were lowest for the Ad26.COV2.S vaccine, but it was associated with greater cellular responses.

"Ultimately, vaccine efficacy/effectiveness studies will have to assess what is most effective and which immune parameters are the best predictors of that effectiveness," Atmar said.

Atmar considered the question of whether the data suggest that a mixed primary series might provide advantage over two doses of the same vaccine."There are theoretical reasons that a heterologous boost—combination of mRNA and adenovirus-vectored--would be more advantageous, but...we'll have to determine the actual relative benefit in larger clinical studies," he commented.