COVID: single dose vaccine post-infection; vit d article retraction
the NY Times had an article arguing for a single dose of vaccine after an actual Covid-19 infection (see https://www.nytimes.com/2021/02/19/health/covid-vaccine-single-dose.html?referringSource=articleShare ).
This article follows a study a few weeks ago, with the associated blog: http://gmodestmedblogs.blogspot.com/2021/02/covid-high-immune-response-to-single.html , a study from Mt Sinai hospital in New York where 41 SARS-CoV-2 seropositive patients had huge increases in spike protein antibody titers after a single vaccine dose (thereby considering this single dose a “booster” vaccine that boosted the antibody response after a prior infection), along with more adverse effects from this single-dose booster (reflecting stimulation/augmentation of their prior immunologic response to the infection)
A new study from Seattle found increased efficacy of a single-dose booster injection for those with Covid-19, with benefit extending to the “South African” variant B.1.351 (see covid vaccine after infection medrxiv021 in dropbox, or https://www.medrxiv.org/content/10.1101/2021.02.05.21251182v1.full.pdf ), in a pre-print, pre-peer reviewed form
Details:
--sera from 10 previously Covid-infected people were tested for neutralizing antibodies against the original Wuhan-Hu-1 and the B.1.351 viral strains, both before and after a single immunization with either the Pfizer or Moderna mRNA vaccines
-- 6 males, 8 white, median age 55, 40% had WHO disease severity scale 3 (still in the mild range), 202 days from symptom onset prior to getting vaccinated, 13 days from first vaccine to postvaccination visit
-- 7 had the Pfizer/3 the Moderna vaccine
-- antibody neutralization experiments used pseudo-viruses expressing the full-length baseline initial Wuhan Hu1 spike, and a spike containing the B.1.351 variant (with multiple mutations, including the N501Y and A701V ones)
Results:
--prior to the immunization, sera from the recovered donors had weak neutralizing antibody to the Wuhan Hu1 strain (and quite variably so, with a 1000-fold difference between donors), but only half could neutralize the B.1.351 strain and also only weakly
-- 16 days post-vaccination (range 13 to 20 days):
-- there was a 500-fold increase in median receptor binding domain (RBD)-specific IgG titers, 200-fold increase in mean RBD-specific IgA titers, though IgM titers were not boosted by vaccination
-- antibody titers corresponded to an increase in RBD- and S-specific IgG memory B cell frequencies, as well as S-specific CD4 T-cell responses (consistent with an anamnestic response to the vaccine)
-- there was a 50-fold increase in binding to both the Wuhan Hu1 and B.1.351 viruses, though binding to the B.1.351 was significantly lower
-- the neutralizing titers were boosted 1000-fold against both the Wuhan Hu1 and B.1.351 strains
-- And these neutralizing titers either before or after immunization were not correlated with the time of symptom onset or Covid-19 severity
-- they also assessed the original SARS-CoV-1 virus, the SARS-causing virus from 2003 (which, as compared to SARS-CoV-2, was 24% divergent in the overall S protein, 26% in RBD, and 50% in the receptor binding motif), and these differences were so divergent in fact that several monoclonal antibodies that potentially neutralize SARS-CoV-2 do not neutralize SARS-CoV-1
-- but, a single dose of either mRNA vaccine elicited SARS-CoV-1neutralizing titers in all donors, though 100-fold lower than against the Wuhan- Hu1 strain.
Commentary:
-- this study found that though there was weak neutralizing antibody activity against the Wuhan Hu-1 SARS-CoV-2 virus 4-8 months after infection, there was a profound increase from a single dose of either mRNA vaccine (Pfizer or Moderna)
-- and, notably, there was an impressive robust response to the B.1.351 variant (even though vaccination with these mRNA vaccines in people without prior infection was less impressive against B.1.351).
-- and, interestingly, also against the quite different SARS-CoV-1 virus (from the 2003 SARS outbreak)
-- which all suggests to me that it might have been better to have multiple antigenic components in the current mRNA vaccines, and not simply the encoded S protein (since the natural infection does potentially evoke an array of antibody responses, and, in other vaccines, having more than one antigen in the mix does seem to be more effective). Though the revaccination with just the S protein (as in these mRNA vaccines) does seem to stimulate this apparently broader response, covering substantially different variants.
-- the NY Times also had an interesting article on the development of a pan-coronavirus vaccine, perhaps including spike proteins from the viruses causing SARS, MERS and Covid-19 (see https://www.nytimes.com/2021/02/09/health/universal-coronavirus-vaccine.html ), and a mouse study suggesting the potential benefit of a multi-antigenic approach: https://science.sciencemag.org/content/371/6530/735 )
--SARS-CoV-2 neutralizing antibodies are present in humans after infection and slowly decline over time (though, we do not know what level of decline might be associated with decreased clinical protection, since there is an anamnestic response whereby antibodies can be generated rapidly to a microbe after a prior infection, even if these antibodies had been below our ability to detect them)
--the majority of these neutralizing antibodies are anti-RBD
--the B.1.1.7, B.1.351, and the P.1 variants all have the N501Y mutation in the RBD, increasing their affinity for the ACE2 receptors, and a D614G mutations that increases the virion spike density and infectivity
--there has been initial concern that several vaccines, including the mRNA ones, have about 5-fold less effect against the B.1.351 variant, and the Astra-Zeneca one in South Africa may well be problematic clinically (see http://gmodestmedblogs.blogspot.com/2021/02/covid-spreading-uk-variant-south-africa.html )
--there was another study assessing the Moderna vaccine in 32 people, 13 of whom had prior Covid-19 infection, finding a robust 47-fold immunologic change after the first vaccine dose (vs 2.6-fold rise in SARS-CoV-2 naive people), but after the second dose the change was 1.4-fold (vs 13-fold in those naive to the virus): see https://www.medrxiv.org/content/10.1101/2021.02.07.21251311v1.full-text . so, a single vaccine post-infection seemed to work better!!
--SARS-CoV-2 infection is mediated by the viral spike protein (S), comprised of an N-terminal S1 domain which includes an N-terminal domain (NTD), C-terminal domain (CTD) and receptor binding domain (RBD). These domains affect different aspects of the infectivity of the virus: the RBD mediates entry/attachment of the virus via ACE2 receptor, CTD contains the fusion machinery
--neutralizing antibody is felt to be an important protection against reinfection, though clear clinical data confirming this are lacking. And having confirming data is really important, since we really need to know if measuring neutralizing antibody in the lab is an appropriate surrogate marker for clinical protection from SARS-CoV-2. (animal models support this). this is important for being able to do quick lab tests to assess vaccine efficacy instead of prolonged clinical trials (recruiting large numbers of patients after making lots of modified vaccine)
--there seems to be a complex inter-relation between these different antibodies. for example, a recent study assessing antibody responses in patients with Covid-19 infections found high cytokines and high anti-RBD antibodies in those with more severe infections, but this anti-RBD antibody level did not fully correlate with neutralizing antibody effects, and it was the high-potency neutralizing ability that correlated with survival (see https://www.cell.com/cell/pdf/S0092-8674(20)31685-8.pdf ). but, we need confirmatory data from larger studies (this had 113 people)
--l must admit that I have trouble referring to the purported sites of origin of the mutations: “UK” (B.1.1.7) or “South African” (B.1.351) or “Brazilian” (P.1) variants, ever since Trump attacked the “Wuhan” virus as a “Chinese” virus and attributed SARS-CoV-2 to Chinese malfeasance. The issue is that this is a global pandemic, variants will emerge all over the place, there should be no stigma attached to whence they evolve, and in fact the US has (related to Trump’s anti-immigrant xenophobia) probably increased the likelihood of developing variants occurring by gobbling up as much vaccine as possible for the US instead of encouraging/supporting/collaborating in a global vaccination initiative from the beginning
--estimates are that there are nucleotide mutations in SARS-CoV-2 at about 1-2/month. and, by the way, this is for a virus that actually has intrinsic mechanisms to self-correct its mutational errors, as opposed to, for example, the HIV virus, which makes an HIV vaccine really difficult to make: dealing with a rapidly moving target...
limitations:
--only 10 people involved in the study, might be nice to have a larger study, in different centers, to affirm generalizability
--as above, not sure what the level of antibodies translates to in terms of clinical effectiveness. and, as with infections in general (even ones with life-long protection), antibody titers do wane over time
--and we need to know if/what neutralizing antibodies are the appropriate surrogate marker for clinical effectiveness
so, this study (and others cited above) do suggest a few conclusions:
--it is important to vaccinate those who had prior Covid-19 infections
--there is increasing evidence that a single injection is the way to go, creating a booster effect after the initial infection, stimulating an array of likely protective antibodies in high titer that (in the laboratory) seem likely to prevent infection even with coronavirus variants.
--there is even some evidence that a second injection in those with prior infection may be less good than just giving one
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also, the vitamin D article sent out a few days ago (http://gmodestmedblogs.blogspot.com/2021/02/covid-vitamin-d-seems-to-decrease.html ), from mdRxiv (the pre-print, pre-peer review site) was retracted for methodologic considerations, some of which i mentioned in the "limitations" section. retractions well happen more often prior to full journal evaluation/review/formal printing (though it also happens after formal acceptance/publication at times). for more info, see:
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