Covid: ?waning vaccine long-term clinical effectiveness

 This is the second blog on vaccine effectiveness, this one assessing the Pfizer vaccine in a US study, finding that the Pfizer vaccine provided continued high effectiveness against severe covid-19 infections: see covid pfizer inc infections but no change hosps Lancet2021 in dropbox, or doi.org/10.1016/ S0140-6736(21)02183-8 

 

 Details: 

--retrospective cohort study from Kaiser Permanente Southern California assessed the Pfizer vaccine effectiveness against SARS-CoV-2 infection and Covid-related hospital admission for up to 6 months, in individuals at least 12yo 

--3,436,957 individuals’ data, from Dec 14, 2020 until Aug 8, 2021

--median age 45 (44% 16-44yo, 31% 45-64yo, 20% >64yo); 52% female; BMI 18.5-25 in 27%, 25-30 in 30%, 30-35 in 19% ; 41% Latinx/32% white/8% Black/12% Asian/10% Pacific Islander 

--comorbidities:  21% hypertension/11% diabetes/9% COPD/8% peripheral vascular dz/rest <5% 

    -- Charlson comorbidity index 0 in 73%, 1 in 14% [ie, quite a healthy population] 

--prior SARS-CoV-2 test positive 2%, prior positive serology 0.1% 

--8911 specimens had whole genomic sequencing, with systematic sequencing after March 4, 2021 

    --they were unable to sequence those with higher cycle thresholds (Ct) on PCR (median Ct value of 31), with the sequenceable ones having median Ct of 23  (the latter having a high viral load)

 

-- 1,146,768 (33%) had received at least one dose of Pfizer and 1,021,516 received at least one dose of Moderna, 109,911 received Janssen, all by August 8, 2021; and 1,166,790 were unvaccinated 

    -- 91% were fully vaccinated and 7% partially 

--mean time since being fully vaccinated was 3.4 months, and 72% were of them were vaccinated at least 3 months before a positive SARS-CoV-2  PCR

 

--Outcomes: SARS-CoV-2 PCR-positive tests from any site in any clinical setting regardless of the presence of symptoms,  and PCR-positive COVID-19-related hospital admissions 

--multivariable models to mathematically adjust results: age, sex, race/ethnicity, prior PCR-positive SARS-CoV-2 test, previous health care utilization (inpatient, outpatient, ED), BMI, acute MI/CHF, cerebrovascular dz, peripheral vascular dz, malignancy, organ transplant, diabetes/renal disease/COPD/hypertension, Charlson comorbidity index, influenza vaccine in prior year, pneumococcal vaccine in past 5 years, and neighborhood deprivation index (an assessment of neighborhood-level socioeconomic status developed in the UK) 

 

Results: 

-- SARS-CoV-2 infections: 184,041 (5%) were infected with SARS-CoV-2, 12130 (7%) of whom were admitted to the hospital 

    -- infections: happened more in younger people (42 vs 45 yo), Latinx (58% vs 40%), obese (44% vs 33%) 

    --hospitalizations: more were older, male, had comorbidities, and more previous health-care utilization 

 

--For fully vaccinated individuals, over the entire study period: 

    -- vaccine effectiveness (VE) against SARS-CoV-2 infection,  adjusted as above: 73% (72–74%)  

        -- age 12-15yo: 91% (88–93%)  

        -- age >64 yo: 61% (57–65%)  

    -- VE against COVID-19-related hospital admissions: 90% (89–92%) 

        --age 16-44: 92% (88–95%) 

        --age >64yo: 86% (82-88%) 

 

--VE against Covid infections in those vaccinated, over time:  

    -- declined from 88% (86–89%) during the first month after full vaccination to 47% (43–51%) after 5 months (>156 days after the second dose), p<0.0001 

        --age >64yo: VE after 1 month of full vaccination was 80% (73-85%), decreasing to 43% (30-54%) at 5 months 

--VE against hospital admission in those vaccinated:  

    -- 87% (82-91%) at 1 month and 88% (82-92%) at 5 months 

        -- ie, significant loss of VE for overall infections but no change for hospital admissions: so, the vaccine is just as effective against severe Covid cases 5 months later (though since infection protection itself waned, more vaccinated people could get the virus, perhaps be asymptomatic or minimally so, but potentially spread it to others) 

 

 

 

Figure 2 from the journal article: top graph is VE against SARS-CoV-2 infection; bottom VE against hospital admission over number of months since being fully vaccinated

 

-- whole genomic sequencing:   

    --delta variant prevalence: 1422 (28% overall, increasing to 87% by July, 2021) 

-- VE, by variant:  

    -- VE against delta variant infections first month after full vaccination: 93% (85–97%) but declined to 53% (39–65%) after 4 months. 

        -- VE against other (non-delta) variants the first month after full vaccination: 97% (95–99%), but waned to 67% (45–80%) at 4–5 months. Differences between the variants was not statistically significant 

    --VE against hospital admissions for delta variant infections for all ages: 93% (84–96%) for up to 6 months. For other variants was 95% (90-98%) 

 

Commentary: 

--this study found that 6 months after full Pfizer vaccination, the protection against hospital admissions for Covid continued at a high level, unabated. However, there was significant waning immunity against becoming infected with SARS-CoV-2.

--there is a reasonable argument that we are moving to a phase of relative truce in the war against Covid for the time being, for the following reasons: 

    -- Covid will likely continue into the distant future, perhaps forever, given the anticipated viral, vaccine and human characteristics: 

        --vaccination will never be complete, given differential access to vaccine around the world, and a significant population of people “hesitant” to get the vaccine in many countries where vaccine is plentiful 

        --with this virus, we cannot go by symptoms to effect a reliable mitigation strategy: a very large % of highly contagious people (+/- 50%) are either asymptomatic or presymptomatic. And, in the winter, viral spread will likely be much worse, when we will have even more effective viral transmission, with some combo of Covid fatigue, more indoor association (with its attendant decreased distancing and decreased ventilation with closed windows), and with other abundant seasonal URIs/allergies to confuse the picture. All of this will influence some people to not worry/not get tested/not isolate themselves for 7-10 days, and this will sustain/propagate the virus in the community (though many people do not have much of a choice:  they cannot get paid time off, and they have families to support and cannot quarantine, so they need to work despite symptoms, potentially spreading the virus to family, friends, coworkers, others they interact with)

        --the current SARS-CoV-2 variants are remarkably transmissible, more so than most other viruses 

        --the virus morphs pretty frequently and future variants are likely to become more transmissible over time (and may also develop more genetic mutations more rapidly than the original SARS-CoV-2 virus which was at a rate of 2 mutations/month: eg see http://gmodestmedblogs.blogspot.com/2021/09/covid-troublesome-new-variant-lurking.html ) for a new variant which is mutating much more rapidly [ie, the current relative equanimity may not last…]

        -- those vaccinated and getting SARS-CoV-2 infection, is skewed dramatically to less severe cases as found above, and see https://www.doh.wa.gov/Portals/1/Documents/1600/coronavirus/data-tables/420-339-VaccineBreakthroughReport.pdf . 

            -- and other relevant blogs: http://gmodestmedblogs.blogspot.com/2021/11/covid-vaccine-effectiveness-in.html  for a recent one finding much lower hospitalization rates and less severe hospital courses in those vaccinated;  http://gmodestmedblogs.blogspot.com/2021/11/covid-vaccine-post-infection-decreases.html for further decreased Covid hospitalizations with vaccination after Covid disease

        --we are in the process of likely approval of a couple of oral meds to treat early in symptoms that give 80ish % decreases in hospitalizations (I have not seen the studies, so cannot comment further). And, there was an intriguing study on fluvoxamine (see http://gmodestmedblogs.blogspot.com/2021/11/covid-fluvoxamine-decreases.html) as well as with the approved monoclonal antibodies. all of this will likely decrease severe covid-19 outcomes (though these meds need to be available globally...)  

       --long covid seem to be much less likely after vaccination 

       --so, barring the development of a SARS-CoV-2 mutation that escapes both vaccine and prior infection, is highly transmissible, and is really severe, we may well be moving into a meta-stable environment…  though we must be vigilant that the continued spread of even our current variants does still pose a significant risk to those susceptible to bad outcomes (elderly, immunocompromised, nonvaccinated for whatever reason, etc)… and, as mentioned in yesterday’s blog, vaccinated people >80yo still have a higher death rate than unvaccinated people <50yo (see http://gmodestmedblogs.blogspot.com/2021/11/covid-vaccine-effectiveness-in.html )

 

--a pre-print, pre-peer-reviewed Canadian study from 2 provinces (11 million people) confirmed vaccine effectiveness against hospitalization at 5-7 months and that a 7-8 week interval between doses improved vaccine effectiveness more than the 3-4 week interval prescribed for the mRNA vaccines (see covid pfizer AZ vaccines cont effective 6 mo in canada medrxiv2021 in dropbox, or preprint doi.org/10.1101/2021.10.26.21265397). Detials (in brief): 

    --in Canada, they used the Pfizer, Moderna, Astra-Zeneca vaccines, the latter one with second dose after 4-12 weeks (>90% got the 2 doses of mRNA vaccine, but with 5% getting A-Z with mRNA as the 2^nd shot) 

    --in British Columbia they extended the interval between mRNA vaccines to 6 weeks and in Quebec to 12 weeks (though in March 2021, Canada’s National Advisory Committee on Immunizations endorsed the delayed second shot to up to 16 weeks; and that those having had a first dose of A-Z vaccine should get a second dose of either A-Z or one of the mRNA vaccines; and that those getting first dose of mRNA vaccine could get second dose with either mRNA vaccine)

    -- 88% of specimens tested were the delta variant 

    --overall vaccine effectiveness: for mRNA in the 90% range, for A-Z at 73% 

        -- but those receiving A-Z then mRNA had 90% VE, supporting the heterologous approach (see http://gmodestmedblogs.blogspot.com/2021/10/covid-mix-and-match-boosters-work-again.html ) 

    -- VE against hospitalization: 98% for mRNA, 94% for A-Z, and similar for the mixed mRNA or A-Z followed by mRNA (these differences were not statistically different) 

        --no meaningful difference by age (including those >70yo), or sex 

    -- in terms of time between 1st and 2nd doses for mRNA vaccines re: covid hospitalizations (data were most robust for the Pfizer vaccine because of their large sample size): 

        -- 3-4 weeks: VE 90%

        -- 7-8 weeks: VE 99%, and remained stable thereafter 

        -- and, by the way, longer intervals have been more effective for other vaccines as well (eg see http://gmodestmedblogs.blogspot.com/2018/02/new-adult-and-pedi-immunization.html , where delaying the 3rd dose to >129 days after the second dose dramatically increased the immune response to the vaccine)

 

Limitations: 

--data from only one (albeit large) group of people in one area of California having the same insurance 

--not lots of comorbidities in the group, and their population was skewed to a younger age than the general population

--followup was still pretty short. Only median of 3.4 months, with data extending only to 5-6 months. We certainly need followup of this cohort to see if/when there is a bump in severe Covid infections over time (though my guess is that most in this group will get the booster, making the results hard to interpret). Though would be interesting to know if those who got mild infections (eg, after 5 months) had more subsequent protection from that infection (ie, does the reinfection "boost" their immunity significantly: maybe these mild reinfections are not so bad???, perhaps the reverse of the conclusion from the study finding Covid infection prior to vaccination led to higher levels of immunity than without prior infection: http://gmodestmedblogs.blogspot.com/2021/11/covid-vaccine-post-infection-decreases.html )

--unclear what the consistency was of which Covid patients were admitted to the hospital (eg, was there bias to admit similar patients who had similar comorbidities but were older, which may be totally reasonable, but would be reflected in the “hospitalization rate”?) 

—as an observational study, we cannot establish causality, just association 

--This study did not have any granular data on mitigation strategies (masks, distancing) that might also skew their results?  

--Were there important differences in who got tested for Covid infection? Some employers require testing, but others not. Perhaps there were also other differences by employer in terms of safety in the workplace? openness to accommodate (and even pay...) people who test positive for Covid??

    -- and the recurrent bottom line issue for all of these studies, esp in the US, is that we do not perform or report systematic covid testing in either asymptomatic or mildly symptomatic individuals, which comprise the large majority of cases. So, these numbers of reported Covid cases do not actually reflect the population reality (and this study did not even have data on why people were tested)… though i would imagine that the hospitalizable severe infection rates are likely pretty accurate 

 

 

So, 

--it is reassuring that the protection from severe covid did not vary by SARS-CoV-2 variant (ie, delta variant did not “escape” from the vaccine protection but was the same as all of the other variants over time)

--it is also reassuring that 6 months after full Pfizer mRNA vaccination there was excellent protection from severe disease, though less so for milder infections (though there is still concern that this protection against severe infection might wane, leading to the cautious approach of recommending booster shots. and there is the added benefit of the neutralizing antibody bump with boosters, which likely will continue the noted initial protection from viral transmission overall)

 

 

geoff

 

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