covid: early treatment regimens work with omicron; impact of boosters; array of immune response

 This blog has three parts:

 

1. Anna Wald (who is head of the Allergy and Infectious Diseases division at the University of Washington) sent me this reference after seeing the blog yesterday: a recent pre-print, pre-peer reviewed study suggested that remdesivir, molnupiravir  and nirmatrelvir remain active against the omicron variant of SARS-CoV-2 and other variants of concern (see covid outpt treatments for omicron biorxiv2021 in dropbox, or  https://www.biorxiv.org/content/10.1101/2021.12.27.474275v1.  

 

details in brief:

-- this in vitro Belgian study assessed the effects of these three medications against various variants of concern (VOCs), by pretreating cells overnight with serial dilutions of these medications, then later infecting the cells with the VOCs (all isolated from patients in Belgium)

    -- nirmatrevir (Pfizer pills): good susceptibility for alpha, beta, gamma, delta, and omicron variants

    -- molnupiravir (Merck pills), they only tested alpha and omicron, with good susceptibility (not sure why other VOCs not tested, not explained in paper)

    -- remdesivir: good susceptibility to alpha, beta, gamma, and omicron; delta not tested (not sure why delta not tested, not explained in paper)

-- so, reassuring laboratory studies suggesting that all of the variants so far seem to be susceptible to these medications, not a surprising finding given that these medications target areas other than the spike protein, where has the largest number of mutations in the variants.

-- of course, the caveat is how well the artificial laboratory measurements correlate with real life situations. And, time and perhaps further studies will tell.

 

--also, another blog reader, Pieter Cohen (co-author of the UptoDate chapter on outpatient Covid), gave me permission to share a 15-minute video he did on the various options for outpatient covid, which was (I thought) really clear and to the point: see https://www.youtube.com/watch?v=g5LFeurr0RQ .

 -- for yesterday's blog, see http://gmodestmedblogs.blogspot.com/2022/01/covid-post-vaccine-infections-long.html 

----------------------------------------------------------

2. A couple of things on booster shots:

-- the CDC just changed their recommendations: the Pfizer vaccine booster can now be given after five months. No change for the Moderna or J&J vaccines (see https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html?s_cid=11706:cdc%20covid%20booster%20dose:sem.ga:p:RG:GM:gen:PTN:FY22)

 

-- There was a very impressive graph sent out by Paul Geltman (thanks, Paul), showing that unvaccinated people in Massachusetts have an exceedingly high rate of Covid infections, those ”fully” vaccinated have a significantly lower rate, and those who have had a booster have an even much lower rate (raising the question again as to whether having a booster after the appropriate interval from last shot should be the real definition for “fully vaccinated”).  

    -- But, hot off the press: the CDC is more nuanced than before, commenting that people should get an appropriate booster dose to remain up to date with their vaccines (see https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html ), though not specifically stating this is considered "fully vaccinated"

 

3. Another recent article assessed the array of immunologic responses to SARS-CoV-2, reinforcing that several immunologic components are durable 6 months after mRNA vaccination (see covid mRNA vaccine durable immune response incl delta science2021 in dropbox or https://doi.org/10.1126/science.abm0829 ) 

  

Details: 

-- 61 people who had received an mRNA vaccine had immunologic testing at baseline and six months postvaccination to assess antigen-specific antibodies (anti-spike, anti-receptor binding domain, and neutralizing), memory B cell, and memory T cell responses 

    -- 16 of these individuals had a prior Covid infection 

  

Results: 

-- antibodies all increased dramatically one month after vaccination, then had a steady decline over the six-month period; these antibody responses paralleled those of a mild infection, though were more profound 

-- memory B cells: mRNA vaccine induced spike- and RBD-specific memory B cells, and they cross-bound alpha, beta, and delta RBDs, and were capable of rapidly producing functional antibodies after stimulation 

    -- the memory B cells continued to increase from 3 to 6 months postvaccination 

    -- the mRNA vaccines were more effective than mild Covid infection in generating a higher frequency of variant cross-binding, with >50% of RBD-specific memory B cells cross-binding alpha, beta, and delta variants, despite their mutations in the binding proteins

--memory T-cells: 

    --CD4 and CD8 T-cell responses decreased in the first few months after the second dose of mRNA vaccine, then stabilized, but were higher than in those with prior mild Covid infection 

--overall, recall responses to an mRNA vaccination in those with prior immunity led to high circulating antibody titers, which correlated with prior memory B-cell frequency

  

Commentary: 

--I bring up this article because it reveals parts of the complex immunological response to a virus, with important interactions between these different components. And that there are still durable antibody responses to antigen re-exposure. this immune memory was noted for the 3 variants of concern that were tested: alpha, beta and delta 

    -- for example, many articles measure neutralizing antibodies, which are an okay surrogate for the immune response (see http://gmodestmedblogs.blogspot.com/2021/06/covid-neutralizing-antibodies-predicts.html ), though they do wane over time.

    -- though not statistically significant in a small study,  a recent Israeli article on health care workers found that the peak neutralizing antibody response soon after vaccination with the Pfizer was more protective against the alpha variant than the levels found just prior to reinfection (see http://gmodestmedblogs.blogspot.com/2021/08/covid-breakthrough-infections-and-assoc.html ), which reinforces the finding in this study that memory cells will awaken the necessary neutralizing antibodies when called to do so (ie, later exposure to the virus) 

    -- a small trial with the Pfizer vaccine found efficacy waning to 84% from 4 to 6 months after dose 2, but 23 participants (including those up to 85 years old) who had significant waning of serum neutralization titers, developed huge increases after the booster (up to seven times as high as it was one month after dose 2!!), See covid pfizer booster inc neut antibodies NEJM2021 in dropbox, or https://www.nejm.org/doi/full/10.1056/NEJMc2113468 ); ie, the memory cells worked in these 23 people. would be good to know if those elderly with strong neutralizing antibody responses early on were clinically protected longterm.

    -- similarly, a booster of the Moderna vaccine (1/2 dose) increased neutralizing antibody titers for both the wild-type virus and several variants tested, including the Delta variant, 2-4 times the level after dose 2 (see covid moderna vaccine booster antibody response naturemed2021 in dropbox, or  https://www.nature.com/articles/s41591-021-01527-y  

        -- a couple of other articles found that those who had neutralizing antibodies had significant boosts in their immune responses by vaccination (see http://gmodestmedblogs.blogspot.com/2021/06/covid-post-infection-durable-immunol.html ) 

    -- another article found that those who had more profound baseline antibody responses were less likely to get reinfection (perhaps suggesting that an initial profound antibody response was associated with a fuller immune response and better protection against reinfection (see 

http://gmodestmedblogs.blogspot.com/2021/05/covid-reinfection-assoc-with-antibody.html ) 

-- it would be great to know in larger studies if: 

    -- those with a high neutralizing antibody response soon after vaccination were really well-protected long-term (ie, did they then have more robust B- and T-cell memory, leading to greater response to being exposed to the virus many months later and have much less severe disease??). and, if so, what is the titer that produces this effect?

    -- how much do the risk factors (age, obesity, diabetes, etc) matter in the initial neutralizing antibody response? if someone with risk factors has a high initial response, are they protected as much as those without those risk factors?

   -- how long does the memory B- and T-cell response remain so robust in leading to strong neutralizing antibodies after later exposure to the virus? this study checked after 6 months. but what about longer? this might affect recommendations on booster shots.

   -- would routine testing of neutralizing antibodies after initial vaccination allow us to fine-tune how we approach booster vaccines? would those with low titers be more amenable to getting boosters? would this more targeted approach be more efficient than just trying to give boosters to all, in a nonspecific way? we don't seem to do really well with mass immunization with several vaccines (tetanus, flu) in adults. would a more targeted approach work better? we do have a targeted approach to hepatitis B vaccine in high risk (eg health care workers), where we check titers to make sure that they are not in the 10% group of nonresponders. maybe for SARS-CoV-2????

so, I bring up this article mostly because it demonstrates more of the complexity of the immune response, and many articles just focus on neutralizing antibody titers, etc.  This article basically shows that the initial antibody response wanes over a few months, but that other components (esp memory B and T cells) are durable and rapidly stimulate antibodies against these 3 variants of concern on later exposure to the virus (the study predated the current omicron variant). And these responses are stimulated by mRNA vaccines as well as mild infections (with the vaccines leading to even stronger responses). But a few other points:

-- it is likely that this immune memory, and the associated rapid antibody response, is part of the reason that SARS-CoV-2 reinfections tend to be mild (eg see http://gmodestmedblogs.blogspot.com/2021/11/covid-infection-protective-new-omicron.html )

-- BUT, this should not undercut the importance of booster vaccinations now. They do seem to decrease reinfections, decrease both symptomatic and asymptomatic infections, decrease hospitalizations and mortality (eg see covid pfizer booster in israel dec mortality nejm2021 in dropbox, or  DOI: 10.1056/NEJMoa2115624) and decrease long covid (see http://gmodestmedblogs.blogspot.com/2022/01/covid-post-vaccine-infections-long.html )

geoff

 

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

 

to get access to all of the blogs (2 options):

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

3. or you can just click on the magnifying glass on top right, then  type in a name in the search box and get all the blogs with that name in them

 

or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center.  This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.

 

 

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list