Covid: Reinfections more likely if prior infection?

Just when you thought that Covid was over (and blogs on covid would stop):

 

Older adults with a prior Omicron infection may have an increased likelihood of reinfection, more than those without a prior infection (see covid omicron infection in elderly assoc with inc risk of reinfection Lancet2023 in dropbox, or https://doi.org/10.1016/j.eclinm.2023.102148

 

Details:

-- 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID In Longer-Term Care Study in Ontario, Canada. The observation period for this study was from July to September 2022

    -- patients were in 27 long-term care and retirement homes in Ontario

-- median age 87, 64% female, 57% in long-term care residence

-- all received 4 mRNA monovalent vaccines (36% had only mRNA-1273, 18% had only BNT162b2, and 46% a mixture), none received a bivalent vaccine; time since 4th vaccination was mean of 138 days, 60% living in residence with <6 outbreaks, clinical frailty score 7 (>6= “living with severe frailty to terminally ill”), number of comorbidities 4, immunosuppressant meds 5%

-- prior to the observation period, 36% had had at least one SARS-CoV-2 infection, 18% (131 of the 750) had an Omicron infection

-- serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titers and spike-specific T cell memory responses were examined in a subset of 318 residents within the three months preceding the observation period

 

Results:

-- during the observation period, 18% (133 of the 750) had an Omicron infection

    -- of those with an Omicron infection in the observation period  57% (76 of 133) had had a prior Omicron infection, whereas for those with no Omicron infection during the observation period 71% (438 of 617) had had no prior SARS-CoV-2 pre-Omicron infection

    -- the cumulative probability of an Omicron infection was highest in individuals with one Omicron infection and no pre-Omicron infection prior to the observation period (p<0.0001)

        -- Having prior Omicron infection: 47.67-times increased risk of subsequent one during the observation period, RR 47.67 (23.73-95.76)

        -- most Omicron reinfections occurred a mean of 156 days after the initial infection

    -- differences in individuals having an Omicron infection during the observation period vs not were:

        -- those getting a mixture of the 2 mRNA vaccines: 28% (37 of 133) had Omicron infection vs 50% (309 of 617) did not get infection. 

            -- having only 4 BNT162b2 vaccinations had higher Omicron infection risk, 37% (49 of 133) vs 14% in those with no Omicron infection (there was a statistically significant benefit of 4 mRNA1273, not so for 4 BNT162b2, though the latter having 30 mcg of mRNA vs the mRNA1237 having 100 mcg)

            -- no difference in number of days since the fourth vaccination

        -- resided in long-term care facilities 82% (109 of 133) vs 52%

        -- residence outbreaks in <7%: 73% (97/133) vs 57%

        -- Clinical Frailty Score >6: 69% (92 of 133) vs 52%, not significant

        -- no difference in number of comorbidities

        -- days since last vaccination: not significant

        -- no difference by  age and sex

 

-- before the start of the observation period, patients with prior Omicron infection (median 101 days before) had increased serum antibodies (anti-spike and anti-RBD IgG and IgA antibodies, and increased neutralization capacity against ancestral and Omicron BA.1 variants). No difference in T cell memory response to the spike protein

    -- BUT, reinfected patients had lower serum neutralizing antibodies to both ancestral and Omicron BA.1 SARS-CoV-2 and lower anti-RBD IgG and IgA antibodies after their initial Omicron infection. 

    -- there were no differences in the immune response to vaccination between those people who were never reinfected with Omicron vs those who were

        -- which all suggests that there were differences in the biological response to the initial infection (and not an underlying immune defect), leading to lower serum neutralizing antibodies to ancestral and Omicron BA.1 and lower humoral antibody responses in those reinfected

Commentary:

-- prior studies have found that previous Covid from the ancestral, Alpha, Beta, and Delta SARS-CoV-2 variants conferred protection against subsequent infection. However, this had been found to be lower for the earlier Omicron BA.1 variant (45% vs 79%), and was associated with a more rapid decline in protection over time, though protection against severe disease remained high (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02465-5/fulltext )

--this current study took place in a very high-risk group for bad outcomes if they get infected with SARS-CoV-2 virus, by being elderly and having lots of comorbidities, and by being in congregate housing

    -- this study was initiated because of the finding of  BA.5 outbreaks in long-term care facilities, and 35% had a prior SARS-CoV-2 infection

-- there was concern about waning immunity in these elderly patients, so a 4th monovalent mRNA dose was offered (and 90% had a 4th vaccine)

    -- they did find that an early infection with the Omicron BA.1/BA.2 variant was associated with an increased risk of developing the Omicron BA.5, though there was protection for the 3 months post infection BA.1/BA.2 (ie, waning immunity soon after the booster)

        -- though, consistent with expectations, those elderly patients who had less robust humoral immune responses to SARS-CoV-2 infection were at the highest risk, suggesting that there were differences in either their initial hybrid immune response

        -- and this study does suggest that there may be differences in the long-term immune response to the Omicron variant (ie waning immunity after vaccination) than with the pre-Omicron SARS-CoV-2, where there seemed to be more lasting protection against reinfection. there may need to be a shorter time interval to revaccination than found in the pre-Omicron variants. Though still unclear why a prior Omicron infection would increase the risk of reinfection so markedly. ?selection bias: those with prior Omicron infection were already at higher risk of getting another one??

 

-- One big question now is the emergence of the BA.2.86 Omicron variant (now nicknamed “Pirola”) and its susceptibility to our vaccinations (and antiviral meds): there are 34 new amino acid differences in the spike protein from BA.2 and 36 more than the recent XBB.1.5): https://www.cdc.gov/respiratory-viruses/whats-new/covid-19-variant.html , and https://www.bmj.com/content/382/bmj.p1964

    -- BA.2.86 has been found in several wastewater samples in the US since August

    -- there are hopeful signs that the upcoming bivalent vaccine will work (https://www.yalemedicine.org/news/5-things-to-know-omicron) ; and, though i cannot find real studies on this, Moderna is stating there is an 8.7-fold increase in neutralizing antibodies in humans against BA.2.86 (https://www.nasdaq.com/articles/moderna-says-updated-covid-vaccine-is-effective-against-newer-variant ). but, the real answer will lie in the actual cases of BA.2.86 and other emerging variants (XBB, EG.5, etc), both prevented entirely by the vaccine or with significantly reduced clinical disease.

 

Limitations:

-- this was a retrospective observational study with some limitations: 

    -- as a non-RCT, there might have been unmeasured confounders (eg other comorbidities, social, of environmental factors) that might limit the generalizabilitiy of the result)

    -- no testing/information on those people who might have had asymptomatic infections

-- there was no granular information of what the comorbidities were, how they were evaluated, how sick the individual was with each of the comorbidities, what medications they were taking for each comorbidity, and if there was a significant interplay between the different comorbidities and subsequent clinical outcome

-- there was no information about the severity of the Omicron infections during the observation period (or before the observation period))

-- the group of patients measured (elderly in facilities) are particularly vulnerable to Covid, limiting generfalization to younger people or community-dwelling elderly

-- there was no genomic sequencing of the virus, so no definitive documentation that the infections were from Omicron, though the timing of the results are highly suggestive

-- they did not measure potential T cell cytokine responses, so the memory T cells may have not been equivalently functional in those getting subsequent Omicron infections

-- this study did not include the upcoming new bivalent vaccine, so there may be differences in clinical response to this new vaccine (see above)

 

So, a few points:

--this study challenges the held belief that prior exposure to Covid, especially in conjunction with vaccination (ie, hybrid immunity), would necessarily boost the immune system and render individuals less susceptible to reinfection, as found with pre-Omicron variants. It is yet another example of actual data undercutting what would seem to make sense, and thereby supporting the importance of actually studying and getting real outcomes for our seemingly well-conceived preconceptions

    -- one cannot assume that protection against one or several prior SARS-CoV-2 variants will necessarily confer protection from a new one in the future (and new ones seem to happen pretty regularly)

    -- or that immunization along with prior infection will have a durable protection (will high-risk people need boosters every 3 months? Or perhaps even sooner? And the “annual Covid booster” is an unlikely outcome (happening as “Covid fatigue” is reaching ever newer heights)???? And  maybe it is time (yet again) to dust off our masks (http://gmodestmedblogs.blogspot.com/2023/02/cochrane-review-critique-dont-get-rid.html )...

 

geoff

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