Prior Omicron BA.1 primary infection alone was the single-most protective event against any (72%) or symptomatic (86%) BA.2 infection, higher than conferred by a pre-Omicron primary infection alone (38% and 51%, respectively) or by even three doses of mRNA vaccine in infection-naïve individuals (46% and 70%, respectively). Hybrid immunity conferred by prior Omicron BA.1 infection plus two or three vaccine doses similarly increased the estimated effectiveness to 96%. Protection was maintained for at least five months post-infection. When the priming infection was a pre-Omicron SARS-CoV-2, the risk reduction of BA.2 reinfection was 38% in unvaccinated individuals, but >85% in those who had received their second or third vaccine dose less than two months earlier, and >70% when these doses were administered two to six months earlier.

In our population of HCWs, 1.7% of cases detected during the BA.2-dominant study period had been previously infected by the Omicron BA.1 variant, a risk four times lower than among those previously infected by pre-Omicron SARS-CoV-2 virus, but still higher than reported reinfection rates before the Omicron surge.^13–15 The Omicron BA.2 sublineage shares multiple mutations with BA.1, but with genetic differences conferring growth advantage and resulting in BA.1 displacement.³ Omicron BA.2 reinfections had been documented using whole genome sequencing as early as 20 days following an Omicron BA.1 primary infection, although such occurrences appeared rare.^16,17

We observed a moderate protection against any (38%) and symptomatic infection (51%) by heterologous pre-Omicron primary infection without vaccination, but a higher estimate for two-dose hybrid immunity (81%). An study from Qatar reported a 46% effectiveness against symptomatic BA.2 infection in individuals with pre-Omicron PI and 55% and 77% if combined with two- or three-dose vaccination, respectively.¹⁸ Protection was >70% against any severe outcome. Their lower estimate for two dose hybrid immunity compared to our results might be potentially explained by a longer time since second dose. Andeweg et al reported in a preprint that effectiveness against BA.2 infection for individuals previously (pre-Omicron or Omicron) infected was 60-80% for two-dose vaccinated less than one to seven months earlier, and 75-80% for three-dose vaccinated less than one to four months earlier.¹⁹ Studies examining protection against Omicron reinfection (BA.1 or any sublineage) have reported that prior pre-Omicron on infection was associated with moderate effectiveness (25% to 47%), but stronger against severe outcome (>80%), and improved with vaccination.^12,18–22 As reported in our study, a third dose among previously infected individuals was associated to a transient increase in protection both against Omicron BA.1 and BA.2 subvariants.^12,19,20

Evidence about cross-protection between different Omicron sublineages is scarce. Preliminary immunologic data show robust neutralizing antibody titers against BA.2 in sera of previously infected by BA.1, that improved in those also vaccinated.^23,24 Few studies to date have estimated real-word cross-protection. We found that prior Omicron infection alone was associated with 72% protection against BA.2 reinfection, and 82% when primary infection occurred 30 to 59 days earlier. In a preprint, Chemaitelly et al evaluated cross-sublineage protection against BA.2 reinfection ≥35 days later and reported that BA.1 was 95% protective against BA.2 reinfection during one to 60 days of follow up.²⁵ Authors adjusted for but did not stratify by vaccine status, failing to elucidate the difference in protection with natural versus hybrid immunity. In their preprint, Andeweg et al reported an estimated ∼70% effectiveness against BA.2 reinfection when the primary infection (without vaccination) was 30 to 59 days earlier, during Omicron-dominant circulation and thus indirectly measuring BA.1 – BA.2 cross-sublineage protection.¹⁹ Authors did not, however, report on two- or three-dose hybrid protection for primary infections occurring during the Omicron period.

In Quebec, as in many other countries with high vaccine coverage, most cases during the Omicron BA.1 surge were two-dose recipients as booster campaigns for the general population unfolded only in response to signals of Omicron immune evasion and surge.⁷ This created a pool of recently infected and/or recently vaccinated individuals with hybrid immunity that was more closely homologous for the infection-induced component. In our population of HCWs, prior Omicron infection combined with two or three vaccine doses was associated with 96% protection against BA.2. Estimated protection was slightly higher against symptomatic infections, and only three hospitalizations were recorded. No other studies to date have directly examined the effect and duration of protection from hybrid BA.1 immunity against descendant Omicron sublineages.

Reported protection against Omicron reinfection conferred by prior pre-Omicron infection waned with time since the last immunogenic event (primary infection or vaccination).^12,20,26 However, data interpretation is challenging due to overlapping changes in SARS-CoV-2 variant circulation, vaccination deployment and time since the priming event (primary infection or vaccination). In our study, we observed waning in the first six months from receipt of the second or third vaccine dose among those with heterologous prior pre-Omicron primary infection (from 88-89% to 72-77%), but not for individuals primed with Omicron BA.1 infection during the shorter five-month follow-up period (stable from 96% to 97%). To our knowledge, no studies with longer follow-up have examined the duration of protection from natural or hybrid immunity conferred by Omicron BA.1 primary infection.

Our study has some limitations. We assigned BA.1 and BA.2 sublineages based on calendar time and provincial phylogenetic analysis and surveillance.⁶ We excluded weeks of Delta-Omicron cocirculation to specifically measure the effect of prior Omicron infection, but still ∼14% of infections during the study period might have been due to the Omicron BA.1 sublineage,⁶ which may overestimate Omicron PI protection against BA.2 reinfection. We defined reinfections based on a ≥30-day interval between positive tests because of data documenting early reinfections during SARS-CoV-2 variant replacement periods.^16,17 Prolonged viral shedding might have been misclassified as reinfections,²⁷ but this would tend to underestimate the protection associated with prior BA.1 infection. Reassuringly, sensitivity analysis using the standard ≥90-day interval did not change our estimates of protection. Asymptomatic or pauci-symptomatic infections may have been undetected before or during Omicron waves, which would also lead to underestimation of the protection induced by past infection. Infection ascertainment bias should be low among the prioritized and repeatedly tested HCWs who had easy and continuous access to NAAT testing. Due to the low COVID-19 hospitalization rate among HCWs, the effect of PI severity as well as effectiveness against severe outcomes could not be estimated. Previous data indicate that protection should be higher and longer lasting against severe Omicron disease.^12,20 The proportion of infection-naïve unvaccinated HCWs, the comparator group for all analyses, was low (<2%), and unmeasured characteristics or exposure behaviours could differ from the other groups leading to residual confusion bias. Reassuringly, our estimates of vaccine and pre-Omicron PI effectiveness are in line with published evidence. Finally, the study was conducted among an actively-working adult population such that results may not be generalizable to children, elderly or immune-compromised adults. Extrapolation of our results to newly circulating Omicron BA.4 and BA.5 or other sublineages requires caution. BA.1 infection-induced neutralizing immunity seems less protective against newly circulating Omicron BA.4 and BA.5 sublineages than BA.2 sublineage, but will likely protect against symptomatic or severe infection with these newly evolving Omicron sublineages.^28,29 Ongoing evaluation of heterologous cross-protection (infection and hybrid infection plus vaccine induced) against emerging dominant variants and subvariants remains important in informing real-time vaccine program adjustments.

In the context of billions of people worldwide already infected with SARS-CoV-2, over half having accrued since Omicron emergence alone, and with much of the global population being now also twice vaccinated,³⁰ our results have important implications for preparedness for potential future waves and timely informing immunization programs. If our findings of substantial and sustained Omicron BA.1 hybrid protection against BA.2 also apply to other emerging Omicron subvariants, then booster doses for twice-vaccinated individuals already infected by BA.1 or BA.2 are likely to be of marginal benefit, particularly against severe outcomes. Such doses may be better oriented toward protecting the more vulnerable globally.