8 Dec 2021 Episode 199 Third dose, nursing homes, HCW, side effects and... omicron of course

Dear colleagues,

Please find more information on importance of third dose for nursing homes and omicron, but also a strong plea to keep non-pharmacological interventions.  

Third dose and nursing home

Ep 199-1:  Barda in Lancet Oct 2021. A third dose of the BNT162b2 mRNA vaccine is very effective in protecting individuals against severe COVID-19-related outcomes (90 %) , compared with receiving only two doses at least 5 months ago.   Obviously, this effect is measured on the short run (weeks after booster) and still in “Delta time”.

Ep 199-2: Pieter Pannus in CID Dec 2021. A very detailed study on various immunological aspects of 2 doses in nursing home residents and HCW, vaccinated with 2 doses of Pfizer:

• SARS-CoV-2 naïve residents had lower Ab responses to BNT162b2 mRNA vaccination than naïve staff = expected.
• No naïve vaccinated resident had neutralizing Ab to the B.1.351 (beta) variant = worrying .
• Cluster analysis revealed that poor vaccine responders not only included naïve residents but also naïve staff = heterogeneity of responses to mRNA in the general population.
• Neutralization and avidity of Ab clearly was higher in infected-vaccinated versus naïve vaccinated, both in residents and HCW.  Levels in infected vaccinated residents = HCW (Fig 1 and 2) = remarkable.

Ep 199-3: David Canaday in medRxiv Dec 2021. Effect of third dose in a similar population. As can be seen in Fig 2, most residents and HCW had close to no neut activity left before the booster, but  it increased to very high levels 2 weeks after the booster, in both residents and HCW (17 to 385 increase see Table 2).  The booster response was still slightly higher in subjects with prior SARS-CoV-2 infection than in those who had not been infected (naïve).    

Side effects

Ep 199-4: Cruz in medRxiv Dec 2021 on cardiac manifestations after mRNA vaccine in > 18 yrs youngsters.

• Myocarditis or pericarditis are very rare: for myocarditis per million it was 12.4 for boys and 1.4 for girls after the first dose, and 49.6 for boys and 6.1 for girls after the second dose.  
• The great majority of cases are mild and self-limiting without significant treatment.
• No data  are yet available on children under 12 years  

Ep 199-5: Alexandra Alvergne in medRxiv Dec 2021 on menstrual changes after either Pfizer or Astra-Zeneca based on survey:

• Rather common: 20 %
• Not dependent on type of vaccine
• Higher by about 40-50 % in women who were smokers or who had been COVID-infected
• Lower by 50 % in oral contraceptive users.
• Diverse experiences: from menstrual bleeding cessation to heavy menstrual bleeding. The most common words include “cramps”, “late”, “early”, “spotting”, “heavy” and “irregular”.

Omicron: reduced sensitivity to neutralization

Ep 199-6: Alexander Wilhem medRxiv 7 dec 2021:

• Omicron clearly reduced sensitivity to 2 doses Pfizer (A) or Astra-Zeneca even + 2 Pfizer (C)
• Loss of neutralization Omicron 6 months after Pfizer, but rescue in 78 % after booster (B)
• Total loss activity by Regeneron monoclonal antibody cocktail (casivirimab/imdevimab) (D)   

Ep 199-7:  Sandile Sele medRxiv 7 Dec SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization:

• Dually vaccinated almost complete loss of neut (as compared to D614G)
• Infected + vaccinated: strong decrease, but still neut capacity present

Ep 199-8: Press release by Pfizer: (based on data from 199-6?)

• Preliminary laboratory studies demonstrate that three doses of the Pfizer-BioNTech COVID-19 Vaccine neutralize the Omicron variant (B.1.1.529 lineage) while two doses show significantly reduced neutralization titers
• Data indicate that a third dose of BNT162b2 increases the neutralizing antibody titers by 25-fold compared to two doses against the Omicron variant; titers after the booster dose are comparable to titers observed after two doses against the wild-type virus which are associated with high levels of protection
• As 80% of epitopes in the spike protein recognized by CD8+ T cells are not affected by the mutations in the Omicron variant, two doses may still induce protection against severe disease

The companies continue to advance the development of a variant-specific vaccine for Omicron and expect to have it available by March in the event that an adaption is needed to further increase the level and duration of protection – with no change expected to the companies’ four billion dose capacity for 2022

Other recent papers on omicron

Ep 199-9: Oran Erster medRxiv 7 Dec 2021: PCR adaptation to specifically recognize omicron, targeting mutations in polymerase, spike and nucleocapsid.  

Ep 199-10: Science journalist Kupferschmidt emphasizes that omicron has already spread everywhere and that non-pharmacological interventions should be strengthened, even if omicron is not more pathogenic, because it is so much transmissible.

Beyond omicron

Ep 199-11: Ellen Callaway in Nature Briefing 7 Dec 2021 discusses a number of models of respiratory viral evolution that SARS-CoV-2 could go. 

• One expectation is that it will reach a “fitness optimum” at some point, implying that new mutations will weaken the virus and, if people develop sufficient immunity against this variant, it will be “tamed”.
• Another, more worrisome possibility is  that it will recombine with other viruses (e.g. the common cold CoV 229E and become even more virulent or escape from immunity.

Ep 199-12: Thomas Peacock (who first published the omicron sequence) still evokes another possibility: insertion of sequences from the human host. He also reminds of many other examples of recombination in Coronaviruses, Orthomyxoviruses, Flaviviruses etc, which have increased the fitness of those viruses…

He then concludes:

Insertions in the SARS-CoV-2 genome are of particular interest as they may have the potential for much greater phenotypic change than mutation or deletion alone:

• A prime example being the original insertion generating the furin cleavage site, which likely contributed to the pandemic potential of the virus.
• Insertion of additional loops in the Spike NTD, or further insertions at the S1/S2 site may have the ability to change the antigenicity or cleavability of these regions.

These types of mutations therefore can act as ‘wildcard’ mutations that are hard to predict.

Ep 199-13: Rui Wang  J Phys Chem Lett. 2021 Dec 7 argues that in a first time, SZRS-CoV-2 evolution was primarily driven by adaptation to the new host (mutations that strengthen infectivity), but more recently, some mutations are driven by escape from antibodies, induced by infection and vaccination.  

Ep 199-14: Yassi medRxiv 7 Dec 2021 follow up of 20,000 HCW over 20 months in Vancouver area

Rigorously implemented occupational health, public health and infection control non-pharmacological intervention measures results in a well-protected healthcare workforce with infection rates at or below rates in the community.

Some conclusions

1. A proportion of elderly residents, but also younger staff of nursing homes shows weak responses to mRNA vaccination.  Antibody levels, avidity and neutralizing capacity is higher after infection + vaccination. All those responses are strongly weaning after 6 months and beyond, but can efficiently be boosted

2. Omicron has clearly escaped more than Delta from waning vaccine-induced antibodies, but less so in previously infected + vaccinated subjects. Similarly a third dose partly restores neutralization capacity.

3. SARS-CoV-2 is evolving rapidly by several mechanisms, including recombination with other viral or animal/human sequences.  It is not clear whether/when it will reach a “fitness optimum”, but it is clearly further escaping from immune control by vaccination only. A significant level of “non-pharmacological interventions” (face masks, physical distancing, ventilation…) will be required, in addition to repeated variant-adapted vaccination.    

Best wishes,

Guido