This is a summary, written by members of the CITF Secretariat, of:

Mwimanzi FM, Lapointe HR, Cheung PK, Sang Y, Yaseen F, Kalikawe R, Datwani S, Burns L, Young L, Leung V, Ennis S, Brumme CJ, Montaner JSG, Prystajecky N, Lowe CF, DeMarco ML, Holmes DT, Simons J, Niikura M, Romney MG, Brumme ZL, Brockman MA.  Impact of age and SARS-CoV-2 breakthrough infection on humoral immune responses after three doses of COVID-19 mRNA vaccinemedRxiv, 2022.08.08.22278494; doi:

The results and/or conclusions contained in the research do not necessarily reflect the views of all CITF members.

A CITF-funded study in preprint, not yet peer-reviewed, by Drs. Marc Romney (University of British Columbia), Zabrina Brumme and Mark Brockman (Simon Fraser University), demonstrated that a third dose of an mRNA vaccine significantly enhanced the magnitude and durability of antibody responses, including among adults over the age of 70, who remained COVID-naïve (those who were not infected with SARS-CoV-2). Their antibody concentrations were comparable to those found in younger healthcare workers (median age of 40 years) who were triply vaccinated.

The findings also suggest that COVID-naïve individuals, particularly older adults, would benefit from a fourth dose within six months of the third. By contrast, those who contracted their first SARS-CoV-2 infection following three doses of vaccine may derive less benefit from a fourth dose within this timeframe.

Key findings:

  • One month after the third vaccine dose, SARS-CoV-2 neutralization activities in older adults were equivalent to those observed in younger healthcare workers.
  • At all time points studied, antibody concentrations and functions specific to the Omicron variant were always lower than those specific to the wild-type (WT, original SARS-CoV-2) variant.
  • At three- and six-months post dose 3, the neutralization capacity against Omicron had declined in all COVID-naïve participants, but more rapidly in older adults than in the younger cohort.
  • Within six months of a third dose, neutralization capacity had declined to undetectable levels in 56% of healthcare workers and 96% of older adults who were COVID-naïve (80% overall).
  • Post-vaccination infections typically boosted antibodies against the WT and Omicron-specific responses higher than those seen after three doses of vaccine alone, illustrating the benefits of hybrid immunity. Those with three doses followed by a SARS-CoV-2 infection also showed higher neutralization capacities against both WT and Omicron strains.
  • Despite the fact that the majority of post-vaccination infections would have been caused by Omicron variants, the concentrations of Omicron (BA.1)-specific antibodies nevertheless remained lower than antibodies specific to the WT virus, even in the hybrid immunity group.
  • Neutralization activity against BA.5 was enhanced following infection, compared to poor activity after vaccine alone. However, neutralization activity against BA.5 remained substantially lower than against the WT and BA.1.

69 healthcare workers and 47 older adults who remained COVID-naïve until at least one month after their third mRNA vaccine dose were studied in this cohort based in British Columbia. Most participants initially received two doses of Pfizer-BioNTech, though most third doses were Moderna. Third doses were received at an average of ~7 months after the second. During follow-up, 43% of healthcare workers and 17% of older adults experienced their first SARS-CoV-2 infection.

Additional studies are needed to assess the durability of hybrid immune responses and to evaluate cross-reactivity against emerging viral variants.