covid: BA.2 taking over

 It seems that the omicron BA.2 variant is spreading rapidly in the world (Europe, Asia; eg Germany has >250K infections a day) as well as the US now, as per the graph below from https://covid.cdc.gov/covid-data-tracker/#variant-proportions . the prevalence of BA.2 is throughout the US but is highest in the Northeast: New York/New Jersey at 39% of the circulating virus and 38.6% in New England. overall the percent of SARS-CoV-2 cases sampled in the US is pretty much doubling every week in the past month and edging out the BA.1 (regular old omicron) variant

and, wastewater sampling, a warning sign that tracks with future covid cases in the next few weeks, has found that 38% of sites in the US have had increases in covid on sampling from Feb 26 to March 8: see the wastewater tracker at https://covid.cdc.gov/covid-data-tracker/#wastewater-surveillance , which surveys 698 wastewater sites across the country. most of these sites are midwest and eastern parts of the country (but will, no doubt, to spread further)

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There have been a few articles of note on the BA.2 omicron variant (which might be renamed at some point if it becomes a true variant of concern).

A study in Denmark compared the BA.1 and BA.2 variants in terms of their relative susceptibility of infection as well as household transmissibility (see covid omicron BA2 more transmissible than BA1 medrxiv2022, a pre-print, pre-peer reviewed document, in dropbox, or doi.org/10.1101/2022.01.28.22270044

Details:

-- in Denmark, the BA.2 variant is rapidly replacing the BA.1 variant as the dominant subvariant

-- transmission dynamics were evaluated using the extensive Danish interlinked country-wide databases, including a registry with everyone in Denmark, results of all antigen and PCR tests, and vaccination records (if only we had these types of inclusive databases here...), between late December and early January. they included people living in households with 2-6 members so that larger care facilities were not included.

    -- 84% of potential secondary cases were checked one time and 60% two times, ie reasonably aggressive assessment of potential secondary cases

-- PCR testing in Denmark does not target S-gene deletion, which is found in BA.1 but not BA.2, but " whole genome sequencing (WGS) is conducted routinely in Denmark" and about 25,000 were done. WGS is more accurate than assessing for SGTF, S-gene target failure. [BA.1, but not BA.2, can be picked up on PCR in other countries because of a difference in a specific spike protein mutation, but SGTF is not specific to BA.2 (eg alpha variant also has this)]

-- main outcomes: to compare the BA.2 vs BA.1 variant in order to quantify their different transmissibilities as it relates to the immune status of the primary cases, and the different susceptibilities depending on the secondary household transmisions

Results:

--8541 primary cases (the first household member with a positive PCR) were identified, with the potential of 17,945 secondary cases (ie people in the same house) in a 1-7 day follow-up

    -- BA.2: 2122 primary cases, 4,587 potential secondary cases and 1,792 actual secondary cases, with secondary attack rate (SAR) of 39%

        -- 51% female, most primary cases 10-30yo/most secondary cases 0-60 yo, household size mostly 2-5

        -- vaccination rates: primary cases 21% unvaccinated/52% fully vaccinated/26% boosted; secondary cases 29% unvaccinated/44% fully vaccinated/34% boosted

    -- BA.1: 6419 primary cases, 13,358 potential secondary cases and 3910 actual cases, with secondary attack rate of 29%

        -- 51% female, most primary cases 10-30yo/most secondary cases 0-60 yo, household size mostly 2-5

        -- vaccination rates: primary cases 16% unvaccinated/59% fully vaccinated/25% boosted; secondary cases 30% unvaccinated/47% fully vaccinated/33% boosted

-- at 14 days of followup, the BA.2 SAR was 42% and the BA.1 was 36%. here is 14-day probability graph which includes comparison with delta variant:

    -- note that in these graphs, not only is the secondary attack rate higher in BA.2, but also is positive more quickly

-- susceptibility of infection, comparing BA.2 to BA.1:

    -- unvaccinated individuals (includes partially vaccinated): OR 2.19 (1.58-3.04)

    -- fully vaccinated (the usual misnomer, since they did not have booster, so not really "fully"): OR 2.45 (1.77-3.40)

    -- booster-vaccinated: OR 2.99 (2.11-4.24)

-- transmissibility of infection to household members, comparing BA.2 o BA.1:

    --unvaccinated primary cases: OR 2.62 (1.96-3.52)

    --fully vaccinated primary cases: OR 0.60 (0.42-0.85)

    --booster-vaccinated: OR 0.62 (0.42-0.91)

        --of note, there was less transmissibility for BA.2 in those fully vaccinated and boostered

-- PCR Ct values (inverse reflects viral load): 

     -- unvaccinated: BA.1 mean Ct value 27.02; BA.2 25.42

     -- fully vaccinated: BA.1 mean Ct value 27.33; BA.2 26.97

     -- booster vaccinated: BA.1 mean Ct value 27.65; BA.2 27.09

        -- note that the viral load of BA.2 was higher than BA.1, which might lead to the more rapid transmission to others at home

Commentary:

-- BA.2 differs from BA.1 by about 40 mutations, including a deletion at position 69-70 of the spike region of BA.1

-- in Denmark, BA.1 was first detected on 25November and BA.2 on 5December2021, but since then BA.2 has been increasing at a faster rate: week 52 of 2021: BA.2 was 20% of cases, in week 2 of 2022 it was 45% (strongly suggesting an evolutionary advantage of this new variant over BA.1)

-- BA.2 has been identified in >40 countries at this point

-- some pretty interesting observations in the above study:

    -- (not shockingly) susceptibility of potential secondary cases to infection was highest among the unvaccinated and lowest in those boosted for both BA.2 and BA.1. so, vaccine does help for both variants (and, pretty low booster rates in Denmark: about 1 in 3 people)

        -- BUT, the effect of vaccination was lower for BA.2 than BA.1, suggesting that there is some decrease in vaccine effectiveness 

    -- overall BA.2 is inherently more transmissible than BA.1, with higher levels of secondary attack rate, controlling for sex, age, household size and immunity group

        -- though part of the issue of increased transmissibility may be the higher viral load (lower Ct values) overall with BA.2, which is even higher in those who are unvaccinated. especially in light of the apparent decreased vaccination effectiveness with BA.2

        -- and, BA.1 had been the most transmissible variant to date, only to be replaced by BA.2

    -- but there is no increase in transmissibility from vaccinated individuals

-- another article on BA.2 came out from South Africa (see covid omicron BA2 vs BA1 medrxiv2022 in dropbox, or doi.org/10.1101/2022.02.17.22271030), which also found that BA.2 had a competitive advantage over BA.1 but that the clinical course was quite similar (ie lower percentage getting really sick: but, with much higher attack rates, still translates to lots of people)

--one issue is that omicron cases are rising quickly in Europe now attributable to BA.2.; Europe has historically been a bellwether for cases in the US, with a delay

Limitations

-- this study took place in one country, where inhabitants may have very different approaches to covid avoidance than in other countries

--they did not incorporate important factors in contagion for SARS-CoV-2, such as mask using indoors, which vaccines were given, distancing indoors, ventilation, proximity to the primary case, comorbidities, nutrition/exercise/stress which might affect susceptibility to infection

--this time period included christmas and new years, which tend to have more social gatherings. would these results apply to other times?

-- there was not complete contact evaluation. we do not know the dynamics of BA.2.  for how long is it detectable? sampling people once or twice might be insufficient for complete assessment of transmissibility (though it was clearly quite high--more than BA.1, which was more than any other previously detected variant)

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so, there is a very real concern that this omicron BA.2 will come back to get us in the US. The overall issues are:

-- this variant is more transmissible and is already increasing pretty dramatically in areas of the US

-- there are preliminary signs by wastewater that many areas in the midwest are already seeing omicron increases

-- the spread in the US is likely to be very rapid, since we have decreased our mitigation strategies so abruptly, especially in terms of mask usage and distancing (we now have crowded bars and restaurants, crowded national and international flights, etc), as well as overall general virus precautions

-- it is not clear whether prior omicron infection will be protective, but even if it is, there are still lots of uninfected people here who will likely be infected by this highly transmissible BA.2

-- early WHO reports have concluded that vaccination is effective, and early data from the UK is that booster vaccine is 77% effective against BA.2. this was not found in the above study, though vaccination did help. we will need further studies to clarify

-- a large part of the issue is that only about 35% of the US has had full vaccination and booster shots, the rest of the population is much more susceptible to transmission (eg see http://gmodestmedblogs.blogspot.com/2021/12/covid-omicron-studies-finally-and.html: for the Pfizer vaccine, 2 doses conferred 34% protection from BA.1, but booster increased that to 76%, still a pretty far cry from the 93% for delta variant, but dramatically better than unboosted people for omicron...

    -- and, so, the recurrent (modified) mantra: vaccinate, vaccinate, then boost. and patients need to be aware that booster shots after the potentially rampant spread of this BA.2 may well take 1-2 weeks to be effective. ie, there is no time like the present.....

geoff

 

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