Covid: mix and match boosters work, again

 The FDA panel unanimously recommended that Johnson & Johnson vaccine recipients get a booster, at least two months after the initial injection (see https://www.nytimes.com/2021/10/15/health/johnson-johnson-vaccine-booster.html ), though the formal FDA recommendation is still pending. A recent preprint, pre-peer-reviewed article assessed the potential utility of the mix-and-match strategy, where the J&J vaccine antibody response was found to be boosted significantly with an mRNA vaccine (see Covid J&J vaccine booster mix and match preprint2021 in dropbox, or https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v1.full.pdf , or doi.org/10.1101/2021.10.10.21264827)

 

Details:

-- phase 1/2 open label clinical trial in 10 US sites of adults who received one of the three approved US Covid vaccines (Pfizer, Moderna, or J&J) at least 12 weeks before, and no reported history of SARS-CoV-2 infection, were randomized to one of the three vaccines as a booster [this was with the Moderna vaccine at full dose, 100 µg per injection)

-- 458 individuals were enrolled, divided into two age groups (18-55yo and >55yo), with about 50 individuals in each group

    -- overall about 50% female, mean age 50 (with range 20 to 85), 85% white/8% Asian

-- primary outcomes: safety, reactogenicity, and humoral immunogenicity on study days 15 and 29 after the booster (as compared to one day prior to the booster)

 

Results:

-- reactogenicity: similar to what was found in the primary series, with injection site pain or tenderness in 70-90%, with only two cases reported as severe (one with Moderna, and one with J&J)

-- unsolicited adverse events reported overall: Moderna 24/154 (15.6%),  J&J 18/150 (12.0%), and Pfizer 22/154 (14.3%). These adverse effects were largely grade 2 or lower, though there were 4 grade three adverse events: vomiting in one person given Moderna; and vomiting, fatigue/abnormal feeling, and insomnia in three given the J&J

    -- overall the incidence of adverse events was quite similar with the different vaccines; malaise/fatigue, myalgia, and headache led the pack at greater than 50% for each of them

 

-- Baseline serum binding antibody: 3 to 15-fold lower in those receiving a single injection of J&J compared to the mRNA vaccines

 

-- see their table 2 for full details, but overview:

    -- any of the three initial vaccines, then given a Moderna booster: 96 to 100% had at least 2-fold rise in IgG serum binding antibody by day 15, and 86 to 100% had at least a 4-fold rise in neutralizing antibody titer at day 15

    -- any of the three, then given the J&J booster: 83.7 to 92% had at least a 2-fold rise in their IgG serum binding antibody level, and 50 to 82% had at least a 4-fold rise in their neutralizing antibodies at day 15

    -- any of the three, then given the Pfizer booster: 98 to 100% had at least 2-fold rise in their IgG serum binding antibody level and 93.8 to 98.0% had at least a 4-fold rise in neutralizing antibody titers at day 15

-- overall day 15 geometric mean titer (GMT) rise in neutralizing antibodies was 10.2-75.9 fold rise with Moderna booster, 4.2-12.5 fold rise with J&J, and 11.5-35.1 with Pfizer (of note, the rise in neutralizing antibody titer in those initially given the J&J vaccine and then boosted with the same J&J vaccine was dramatically lower than any other combination tested, with a 15 day GMT of 31, with all of the rest being above 200 [a prior study and found that a level of >100 was associated with a 90.7% vaccine efficacy for preventing symptomatic Covid disease]

 

-- Neutralizing antibody responses against the Delta and Beta variants were only available in those boosted with Moderna vaccine. Pre-booster neutralizing antibody levels were lower for the Delta and Beta variants. But all 4 with Delta and 2with Beta had at least 4-fold increases in neutralizing antibody titers after the booster

  

Commentary:

-- the argument for booster vaccination is basically that there are several studies suggesting waning immunity after vaccination, the spread of the much more highly transmissible Delta variant (which seems to increase the likelihood of breakthrough infections), a not-particularly-good Israeli study suggesting increased protection from a Pfizer booster after initial the Pfizer vaccination (see http://gmodestmedblogs.blogspot.com/2021/09/covid-israeli-study-on-booster-not-so.html ), and another observational study finding the J&J vaccine did have lower effectiveness against both hospitalization and emergency department visits than the mRNA vaccines (see http://gmodestmedblogs.blogspot.com/2021/09/covid-vaccine-effectiveness-in.html )

    -- for example 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 )

    -- 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

-- and, as background, the initial study after a single dose of the J&J vaccine did suggest that it was less effective than the mRNA vaccines (see http://gmodestmedblogs.blogspot.com/2021/04/covid-j-vaccine-viral-load-after-vaccine.html ), with efficacy rates in the low 70% range

-- this current study did find that all three vaccines and all three boosters did reasonably well, though, again, it does seem that the J&J booster did a bit less well than the mRNA boosters, even for those who had an initial J&J vaccination:

    -- they found that the neutralization activity against the D614G pseudovirus:

        -- homologous boost (ie, using the same vaccine as a booster as in the initial vaccination) increased neutralizing titers 4.2-20 fold

        -- heterologous boost increased titers 6.2-76 fold

    -- and, perhaps not so surprising that a booster eliciting a somewhat distinct antibody production might increase the breadth/intensity of the immune response

    -- this study also seemed to find that at least for the Moderna and J&J vaccine, there was a trend to better booster response in neutralizing antibody levels if a different vaccine were used as booster:  though some overlapping confidence intervals, 86% of those who were initially given the Moderna vaccine had a 4-fold increase vs both those initially given J&J or Pfizer who had 100%; those given initial J&J had a 50.0% 4-fold increase with J&J booster but a 61.2% with Moderna and 82.0% with Pfizer (again, small numbers and some overlapping confidence intervals, though the 50.0% seemed to be significantly lower than what the Prizer booster elicited)

-- we vaccine consumers are limited to results derived from the drug company-sponsored studies, where the Pfizer vaccine had two doses three weeks apart, the Moderna two doses four weeks apart, and the J&J a single dose. These protocols were derived from a variety of scientific inputs, best guesses, and (likely) marketing (i.e., the niche of a single-dose vaccine has several marketing advantages, including price of the vaccination schedule, as well as ease of administration, handling of the vaccine, etc.). But, in any event, in general we need to follow the protocols of these studies, since untested other protocols may be less efficacious (or more???)

-- a recent very small study of 31 participants who received two doses of the Pfizer vaccine, 20 who received two doses of the Moderna vaccine, and 8 getting one dose of the J&J vaccine found pretty different kinetics of the immune response elicited by these vaccines, with lower initial IgG antibody responses (including neutralizing antibody response) to the J&J vaccine, but less waning of the response over an eight month period; the CD4 and CD8 T-cell responses were at least as good with the J&J vaccine (see https://www.nejm.org/doi/full/10.1056/NEJMc2115596 )

-- there was also a prior mix-and-match study done in the UK, finding some benefit from giving the Pfizer booster shot to those who received the initial AstraZeneca vaccine (this is the adenovirus-vectored vaccine used in the UK, similar to the J&J vaccine week give here), see http://gmodestmedblogs.blogspot.com/2021/07/covid-mixing-and-matching-vaccines.html

 

Limitations:

-- small number of people involved in each of these nine cells (one of the three vaccinations initially, followed by one of the three boosters), limiting generalizability. For example, the sample size was not large enough for inter-group comparisons

-- no data on the specifics of the individuals involved, such as underlying morbidities or any other sociodemographic variables other than age (and they did not stratify results by age in this paper. likely more data later...)

-- as with all laboratory-based assessment of antibodies, including neutralizing antibodies, this does not necessarily translate into real-world clinical protection, given the complexities of the immune response. The studies have suggested that neutralizing antibodies are a particularly important marker (see http://gmodestmedblogs.blogspot.com/2021/06/covid-neutralizing-antibodies-predicts.html ), though less clearly so for preventing severe infection and death. There was also no measurement of other aspects of the immune system, including the T-cell responses

-- they do not have results for the immune responses to boosters at day 29. (also, likely more data later)

-- some of these participants may have had a mild or asymptomatic Covid infection at some time after the primary vaccination, which might have affected the results

-- these data largely predate the emergence of the Delta variant, so generalizability of these results to our current situation is unclear. And the Delta variant is associated with lower neutralizing antibody levels compared to earlier SARS-CoV-2 infections (though the Moderna vaccine seems to be protective against hospitalization and death from the Delta variant, a bit less clear with Pfizer)

 

So, this study, though limited by only measuring antibody responses, did confirm a few things:

-- antibody levels prior to the vaccination were lowest in those with the J&J vaccine

-- all of the vaccines given as a booster did elicit amnestic responses after the primary vaccination series was given

-- antibody titers were in general higher in those who were given an mRNA booster over J&J booster, even in those initially given the J&J vaccination (ie, it seemed beneficial to give an mRNA booster to a J&J vaccine recipient)

-- booster vaccinations again appeared to be safe, with no evidence additional safety concerns

-- and, there does not appear to be any down-side to mixing vaccines as boosters, especially in those getting an initial J&J vaccine....

geoff

 

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