covid: ?2nd booster

 

There is considerable controversy regarding the utility of a second booster shot in those over 50 years old, as recommended by the CDC. Will review the recent Israeli study on the second booster. (see covid booster 4th dose israel NEJM2022 in dropbox, or https://www.nejm.org/doi/full/10.1056/NEJMoa2201570 ).

 

Details:

--On January 2, 2022, Israel began administering the fourth dose of the Pfizer vaccine to people at least 60 years old

    --This was the time when the omicron variant was predominant in Israel (January 10 through March 2, 2022)

-- 1,252,331 people in the Israeli Ministry of Health database were accessed

-- 4-dose group (boostered, at least 4 months after 3^rd shot): 23,935,905 person-days; age 60-69 33%/70-79 43%/ >79yo 25%

-- 3-dose group (no second booster): 31,000,299 person-days; age 60-69 52%/70-79 32%/ >79yo 16%

-- internal control group (boostered, but within 3-7 days and booster shot not likely taking effect): 2,673,874 person-days; age 60-69 34%/70-79yo 41%/ >79 25%

-- primary outcomes: the rate of confirmed infection as well as severe Covid was assessed starting eight days after receipt of a fourth dose (4-dose group) as a compared to those receiving only three doses (3-dose group) as well as those receiving the fourth dose but 3 to 7 days earlier (internal control group)

 

Results:

--cases of severe Covid, per 100,000 person days (unadjusted):

    -- 4-dose group: 1.5

    -- 3-dose group: 3.9

    -- internal control group: 4.2

-- cases of severe Covid, per 100,000 person days in fourth week after fourth dose:

    -- 4-dose group: 1.6 (1.2-2.0)

    -- 3-dose group: 5.5 (5.2-5.9)

    -- internal control group: 3.6 (3.0-4.5)

-- adjusted rate of severe Covid, in the 4^th week after the 4^th dose in the 4-dose group:

    -- 3-dose group: 3.9 times lower in the 4-dose group than the 3-dose group (3.4-4.5)

    -- internal control group: 2.1 times lower in the 4-dose group the internal control group (1.4-3.0)

-- adjusted rate of severe Covid, in the 4^th week after the 4^th dose in the 4-dose group:

    -- vs 3-dose group: 3.5 times lower in the 4-dose group than the 3-dose group (2.7-4.6)

    -- vs internal control group: 2.3 times lower in the 4-dose group than the internal control group (1.7-2.3)

-- protection did not wane during the six weeks after the receipt of the fourth dose; and there was a trend towards increasing benefit by week six, eg:

 

-- cases of confirmed Covid infection, per 100,000 person-days:

    -- 4-dose group: 177, adjusted rate 171 per 100,000 person-days (165-177)

    -- 3-dose group: 361, adjusted rate 340 per 100,000 person-days (337-343)

    -- internal control group: 388, adjusted rate 308 per 100,000 person-days (299-317)

-- adjusted rate of confirmed Covid, as compared to the 4-dose group, In the fourth week (22 to 28 days) after the fourth dose:

    -- 3-dose group: 2.0 lower in the 4-dose group than the 3-dose group (1.9-2.1)

    -- internal control group: 1.8 times lower in the 4-dose group than the internal control group (1.7-1.9)

    -- this protection did wane after 4 weeks

 

Commentary:

-- this study did document that there was a 2-fold lower incidence of confirmed infection after the 4^th booster (though that waned within a few months) but a 3-fold lower incidence of severe disease, which seemed to be longer lasting (some waxing and waning of effect in those getting the 4^th dose, with apparent increased severe disease over time in those not boosted)

-- The US data per the CDC, from the VISION network (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853475/: for omicron, there was waning immunity against ED/urgent care encounters as well as hospitalizations:

    -- the VISION network involved 8 US sites, assessing vaccine effectiveness against ED/UC visits and hospitalizations, analyzing 3,911 unvaccinated, 3619 vaccinated with any 2 mRNA vaccines, and 2,833 with any 3 mRNA vaccines during the omicron period, finding:

    -- after 3 doses of mRNA vaccine, vaccine effectiveness:

        -- <2 months: 87% (85-88%)

        -- 2-3 months: 81% (79-82%)

        -- 4 months: 66% (59-71%)

        -- >5 months: 31% (-50 to 68%)

        -- trend for waning effectiveness, p< 0.001

 

Limitations:

-- it is important to note that this Israeli study was not a randomized controlled trial. This was an observational study of people who did versus did not get the fourth dose of the vaccine. And, there may well be very important differences between those who elected to get the vaccines that might have influenced the results. eg: were those given the 4^th dose more likely (or less likely) to avoid Covid exposures? were there other differences in behavior patterns that could influence outcomes? were they more likely (or less likely) to have comorbidities, which some people may see as vulnerabilities to infection, and others were so fed up with the whole process and their increased vulnerability to fatalistically decline the vaccine? was there a difference in the 2 groups as to taking antiviral meds (eg paxlovid) that might well have altered the development of severe symptoms?

-- the boostered group was older. But, there was no other information about demographics provided, or comorbidities, including in the supplementary materials. it would be important to see which groups benefited the most from the 4^th shot: older? diabetics? other comorbidities that increase severe covid risk? also, should we consider boosters in younger people (especially given the risk of long covid, which presumably would be decreased if not infected. A lot of long covid happens with only mild disease, though less often: see http://gmodestmedblogs.blogspot.com/2022/03/covid-cardiovasc-outcomes-at-1-yr.html )

-- the Israeli study only has data for the first 6 weeks or so of protection against severe covid. we really need longer-term data to be sure that there is a significant benefit

-- would the same benefit apply to other non-Pfizer vaccines? seems pretty likely, but there could be vaccine divergence as we descend into the ongoing increases in viral mutations and the possibility that differences in the array of vaccine targets of the different vaccines might lead to different outcomes...

 

so, though this data is not rock-solid, there are pretty convincing data from Israel that there is significant protection against severe illness from a 4^th booster given more than 4 months after the 3^rd dose, with major decreases in severe covid infection. and this protection is increasing over a 6-week period.

-- the good news: the trend is to greater protection in this time-frame

-- the bad news is that we do not have a long enough time period to really assess the risks/benefits fully (though rather likely that benefits outweigh risks, esp since it is the same vaccine as the first 3 doses)

-- the US data confirms decreasing protection after the 3^rd booster after about 4 months. this finding should support the benefit of the 4^th booster

-- the best guess based on this confluence of data is that the 4^th vaccine is likely very important, especially in those at higher risk

geoff

 

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