covid: decreased viral load in breakthru infections

 A detailed article from Qatar found a significantly decreased SARS-CoV-2 viral load in those with either vaccine-associated breakthrough infections or subsequent Covid reinfections in unvaccinated people (see covid breakthru dec viral load NatComm2022 in dropbox, or https://www.nature.com/articles/s41467-022-28199-7)

 

Details: 

-- the databases for the study included:

    -- the national cohort of all 384,452 quantitative PCR values for confirmed primary infections since the epidemic began in February 2020 until the end of the study July 11, 2021

    -- the national cohort of all 1695 quantitative PCR values for confirmed SARS-CoV-2 reinfections

    -- the national cohort of all 898,648 vaccinated with the Pfizer vaccine since the first recorded vaccine December 16, 2020

    -- the national court of all 468,872 vaccinated with the Moderna vaccine during this same period

-- Pfizer vaccine: 4777 breakthrough infection in those fully vaccinated, 0.61% of those fully vaccinated

-- Moderna vaccine: 306 breakthrough infections in those fully vaccinated, 0.09% of those fully vaccinated

 

-- during the time period of the study, the alpha and beta SARS-CoV-2 variants were most prevalent, with the beta variant most diagnosed

-- quantitative PCR measures the cycle threshold (Ct), which represents the inverse of the viral load

-- overall, the best correlation between PCR Ct and viral transmissibility is when Ct <27 (see http://gmodestmedblogs.blogspot.com/2022/01/covid-infectivity-of-variants.html )

 

Results: 

-- study groups assessed (highlighted numbers are above their CT 27 threshold for transmissibility:

    -- study one: primary infections in unvaccinated individuals versus Pfizer vaccine: 4035 people, mean PCR Ct 24.0 (23.8-24.2) versus 25.0 (24.8-25.2), difference 1.0 (0.7-1.2), p<0.001

        -- symptomatic infections: 1566 people, mean PCR 22.5 versus 22.7, nonsignificant difference

        -- asymptomatic infections: 1584 people, mean PCR 25.5 (25.2-25.8) versus 26.8 (26.5-27.2), difference 1.3 (0.9-1.8), p<0.001

 

    -- study two: primary infections in unvaccinated individuals versus Moderna vaccine: 265 people, mean 26.8 (25.9-27.6) versus 30.3 (29.6-31.0), difference 3.5 (2.5- 4.5) p<0.001

        -- symptomatic infections: 46 people, mean PCR 21.7 (20.0-23.3) versus 26.6 (24.6-28.6), difference 4.9 (2.3-7.4), p<0.001

        -- asymptomatic infections: 158 people, mean PCR 28.0 (27.0-29.1) versus 31.2 (30.4-32.1), difference 3.2 (1.9-4.5), p=0.003

 

    -- study three: Pfizer vaccine breakthrough infections versus Moderna vaccine breakthrough infections: 227 people, mean 27.1 (26.2-28.0) versus 30.2 (29.4-31.0), difference 3.1 (2.0-4.2), p<0.001

        -- symptomatic infections: 39 people, mean PCR 21.3 (19.3-23.2) versus 26.6 (24.5-28.7), difference 5.3 (2.6-8.1), p<0 .001

        -- asymptomatic infections: 140 people, mean PCR 28.7 (27.6-29.9) versus 31.0 (30.0-32.0), difference 2.2 (0.9-3.6), p=0.003

 

    -- Study four: primary infections in unvaccinated individuals versus reinfections in unvaccinated individuals: 1686 people, mean 24.2 (23.8-24.5) versus 27.9 (27.6-28.3), difference 3.8 (3.4-4.2), p<0.001

        -- symptomatic infections: 364 people, mean PCR 22.7 (22.1-23.3) versus 26.5 (25.8-27.2), difference 3.8 (2.9-4.7),  p<0 .001

        -- asymptomatic infections: 987 people, mean PCR 24.8 (24.3-25.2) versus 28.8 (28.4-29.2), difference 4.0 (3.5-4.5), p<0.001

 

    -- study five: Pfizer breakthrough infections versus reinfections in unvaccinated individuals: 761 people, mean 26.0 (25.5-26.4) versus 27.7 (27.2-28.1), difference 1.7 (1.1-2.3) p<0.001

        -- symptomatic infections: 204 people, mean PCR 23.7 (22.9-24.6) versus 25.6 (24.6-26.5), difference 1.8 (0.6-3.0), p=0.003

        -- asymptomatic infections: 421 people, mean PCR 27.0 (26.3-27.6) versus 28.9 (28.3-29.5), difference 2.0 (1.2-2.8), p<0.001

 

    -- Study 6: Moderna breakthrough infections versus reinfections in unvaccinated individuals: 85 people, mean 28.8 (27.3-30.3) versus 30.8 (29.7-32.0), difference 2.1 (0.3-3.8), p=0.022

        -- symptomatic infections: 13 people, mean PCR 23.5 (19.6-27.4) versus 30.0 (26.2-33.7), difference 6.4 (-0.04 to 12.9), p=0.051

        -- asymptomatic infections: 60 people, mean PCR 30.0 (28.3-31.7) versus 31.7 (30.5 -32.9), difference 1.7 (-0.3 to 3.7), p=0.096

 

-- overall linear regression adjusting for age, sex, nationality, reason for PCR testing, and calendar week of PCR testing:

    -- primary infections in unvaccinated individuals: 301,424 people, using that as a reference:

        -- reinfections in unvaccinated individuals: 3.67 (3.38-3.96), p<0.001

        -- Pfizer vaccine breakthrough infections: 0.82 (0.63-1.01), p<0.001

        -- Moderna vaccine breakthrough infections: 3.29 (2.58-4.00), p<0.001

    -- these results were consistent with the above ones: highest PCR Ct values (lowest viral loads) in this adjusted analysis were for reinfections in unvaccinated people, followed closely by Moderna vaccine breakthrough infections, with Pfizer lagging significantly

 

Commentary: 

-- though this article predated the omicron and much of the delta infections, it provides lots of granular information about the effects of natural infection as well as vaccine-induced immunity in decreasing viral load and likely transmissibility of SARS-CoV-2

-- Qatar has a large database of quantitative PCR values for SARS-CoV-2

-- and, this study had impressive amounts of information for both symptomatic and asymptomatic infections, where >50% of the infections uncovered were in asymptomatic people who were tested for a variety of reasons: part of a survey (random testing campaigns), routine health care testing, pre-travel requirements, port of entry testing on arrival to Qatar), though not a systematic assessment of asymptomatics

 

-- general conclusions:

    -- the viral loads are lower in those who had breakthrough infections, either if they were vaccinated previously or had prior Covid infection

    -- so, the risk of viral transmission is likely much lower in those with breakthrough infections, though a Danish study found that there was still a non-negligible household transmissibility with high Ct values (see Association between SARS-CoV-2 Transmissibility, Viral Load, and Age in Households | medRxiv : finding about 47% transmissibility at Ct of 18 but still 9% at Ct of 38

    -- overall viral loads were lower in those who were asymptomatic (but we do not have systematic multiple samplings, so not sure if the quantitative PCR in asymptomatic people reflected the peak viral load or was already waning)

    -- there seems to be a hierarchy of infectiousness of the virus:

        -- primary infection in unvaccinated person are the most infectious (lowest Ct value), then those getting Pfizer vaccine, then those getting Moderna vaccine, then those unvaccinated who have reinfections after a primary infection (the latter two had overlapping confidence intervals)

        -- and, in terms of the efficacy against acquisition of infection: highest in those with a prior infection, then Moderna, then Pfizer (the inverse)

-- some studies have suggested that assessment of the PCR Ct values not only correlate inversely with viral load, but also with culturable virus (eg see https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.32.2001483, for an early study from England)

    -- however, a more recent study from Switzerland did not find this correlation between quantitative PCR and culturable virus to be true http://gmodestmedblogs.blogspot.com/2022/01/covid-infectivity-of-variants.html . The reality is that PCR picks up live as well as dead virus, and when people are sampled at different times during their infection, there might well be different relative amounts of live vs dead virus

--it is not so surprising that the immunity after a primary infection in an unvaccinated person is the most protective (highest Ct, lowest viral load), since an actual infection does create a broad array of antibodies against the virus (vs just the spike protein, targeted in the mRNA vaccines). And, related to that, the combination of the mRNA vaccine with a more diverse antibody response from a potential T-cell vaccine may yield better clinical results than the current mRNA vaccines (see http://gmodestmedblogs.blogspot.com/2022/01/covid-new-t-cell-vaccine-in-works.html )

-- a prior study in Qatar found that vaccination after a prior Covid infection was associated with a much lower rate of reinfection than those who were just fully vaccinated (see http://gmodestmedblogs.blogspot.com/2021/11/covid-vaccine-post-infection-decreases.html )

  

Limitations:

-- this study has info from before the onslaught of delta, and well before omicron. Though this limits generalizability to these later variants of concern, this study does have unusual granular info about the difference between symptomatic and asymptomatic SARS-CoV-2 viral loads

-- there were pretty dramatic differences with Moderna and Pfizer vaccines, with Moderna way better. why?

    -- the number of infections after vaccination was quite low, especially in those having had the Moderna vaccine, to provide very reliable results (though it was actually a good thing that Moderna had so few infections!!)

    -- there might be a bias as to whom the Pfizer vs Moderna vaccine was given (this was not a randomized trial), which could distort comparisons

    -- we do not know specifics about the timing of vaccine. it is likely that the Pfizer vaccination was completed earlier than the Moderna one (the shots being 3 vs 4 weeks apart) and there might have been more waning immunity after Pfizer. would be good to know the actual timing of reinfections post-vaccination from 14 days after the 2^nd shot.

    -- and we do not have any systematic information about asymptomatic infections. would need to have multiple samplings to make sure that we are comparing maximal Ct's in each of the groups and not just some early vs late in the infection when Ct's vary a lot (and, presumably, viral transmission)

-- the study was done in one location, Qatar, and may not be generalizable to other areas where there may be different demographics, socioeconomic factors, comorbidities, etc. 

    -- eg, Qatar has a particularly young population, with only 9% of its residents being at least 50 years old, and also 89% are ex-patriots residing in Qatar on work visas from more than 150 countries, mostly male 

    -- would be great to see a breakdown of reinfections by the known comorbidities leading to worse clinical scenarios (diabetes, obesity, immunocompromise, etc.)

    -- would also be good to know differences in use of masks, distancing (mitigation strategies) as well as other sociodemographic variables (of course, there were so few reinfections that there might not have been sufficient numbers of people in each category to get statistically significant results)

 

So, despite the fact that this study was done based on older data, and the predominant variant of concern was the beta variant, this study does suggest that immunity from prior infection in unvaccinated people is pretty profound and associated with quite low viral loads (and presumably the public health benefit of decreased transmissibility), and that the mRNA vaccines are almost as good as actual infection (especially Moderna, in this study).  

Of course, there is the limitation that these results were early-on, limiting generalizability to the newer variants as well as assessment for later waning immunity/role of booster/etc. Newer studies are needed. But as with all things Covid, the clinical evaluations (especially as extensive as this one) lag considerably behind the peak of the newer variant’s effects.  Omicron, for example, has only been around a couple of months (and only significantly present for about 1 month in the US). it takes a while to acquire the necessary data for analysis. So the best data we have is the detailed analyses of variants gone by...

geoff

 

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