Tue, 09/07/2021 - 19:48
Dear colleagues,
As promised, here are a few “miscellaneous” papers, some of you may have seen already or have escaped from your attention. As always, I try to present the original papers and give some perspective.
The newest variant of concern from South-Africa C.1.2
Ep 170-1: Scheepers et al report in medRxiv on 26 August on a “descendant” from one of the circulating strains (C.1) during the first wave that has acquired additional mutations. It has 14 mutation in S of which:
- 5 in the N-terminal domain: C136F, Y144del, R190S, D215G and 242-243del
- 3 in receptor binding domain Y449H, E484K and N501Y
- 3 adjacent to furin-cleavage N679K and T716I
- 3 “others”: P9L, D614G, H655Y and T859N
Mutations have also accumulated in ORF1ab, spike, ORF3a, ORF9b, E, M and N proteins (see Fig 2a)
As you may have seen, this is another example of “convergent evolution”, as half of all C.1.2 mutations are also present in other variants of concern (VOC) or of interest (VOI):
- N501Y in alpha, beta and gamma: linked to higher ACE-2 binding
- E484K in beta, gamma and Eta: linked to immune escape
- T478K: in delta
The rise of this variant in South-Africa (0.2 % in May, 1.6 % in June and 2.0 % in July) is similar to the early dynamics of beta and delta.
It has spread to Democratic Republic of the Congo, Mauritius, New Zealand, Portugal and Switzerland
The inferred evolution rate is worrying: emergence of the C.1.2 lineage resulted from a rate closer to 1.4x10-3, or ~41.8 mutations per year, which is 1.7-fold faster than the current global rate.
We are waiting for more data on escape from neut Ab, viral dynamics and clinical characteristics
“Rogue” auto-antibodies to type 1 IFN
Ep 170-2: Bastard et al, who described these Ab already in 2020 explored it further and found:
Auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma):
- Present in 13.6% critical COVID-19, including 21% > 80 years, and 6.5% severe COVID-19.
- These antibodies are also detected in 18% of the 1,124 deceased patients
In healthy individuals:
- Auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years.
Is vaccine efficacy rapidly waning? An alarming question raised by many
Ep 170-3: Jeffrey Morris explains step by step how the apparent vaccine efficacy of Pfizer against severe disease/hospitalization is only 67 %, but in fact remains > 85 %. The “trick” is age-stratification (> or < 50 years), with a different vaccination rate in both age strata. I provide the core Table, but please read the whole argument about “Simpsons paradox”, due to confounding factors.
Ep 170-4: Similarly reassuring data on vaccine efficacy against severe disease in the US during “delta period” (weeks 13-24: 84 %) versus alpha (weeks 2-12: 86 %). Also sustained (but lower) efficacy in risk groups.
Ep 170-5: Tober-Lau in medRxiv 26 Aug illustrate waning immunity in elderly AND HCW, lower durability of both ant-S1 IgG, delta pseudovirus neutralization and Interferon gamma productionby T cells in a cohort of elderly versus HCW at 6 months after Pfizer vaccination.
Ep 170-6: Skelley et al in Nat Comm 19 July: “Two doses of SARS-CoV-2 vaccination induce
robust immune responses to emerging SARS-CoV-2 variants of concern”
A very nice paper, confirming that, after mRNA vaccination, antibody responses against beta and gamma are lower than against previous strains, but still very high and that T cell responses against more conserved parts of Spike are preserved.
Notes: Delta not included
Neutralization only measured as “ACE2-binding inhibition” (hence no virus neutralization)
T cell responses = ELISPOT: still very unclear whether this is a “correlate of protection”
Ep 170-7: Patalon in medRxiv 31 Aug on the very preliminary efficacy of a 3rd Pfizer dose in Israel in terms of new Delta infections using retrospective test-negative and matched case-control analyses:
- 48-68% reduction in the odds of testing positive for SARS-CoV-2 7-13 days after 3rd dose
- and 70-84% reduction 14-20 days after the booster compared to two doses.
They do recognize the limitations:
- short-term retrospective and preliminary results,
- only evaluate marginal effectiveness against infection rather than severe disease.
The total benefit of the vaccine program will depend both on the long-term effectiveness
of the first two doses of the vaccine, accounting for waning, and the marginal improvements conferred by receipt of the booster.
Ep 170-8: Interesting debate in Scientific American on the booster shot:
- Everybody agrees that getting more people a 2-dose vaccination is most important and that a third dose should be given to immunocompromised people
- Biden has decided to offer a third dose of the mRNA vaccines to those who have been vaccinated > 6 months ago: better safe than sorry
- This decision is debated from ethical and medical perspective.
Large randomized trial on effect of masking in Bangladesh
Ep 170-9: The Impact of Community Masking on COVID-19: A Cluster-Randomized Trial in Bangladesh (non-peer reviewed)
A reduction of symptomatic and seropositive (antibody +) SARS-CoV-2: 11.2 % overall, but 34.7 % in 60+
Clearly, mask wearing is only one element of the “Swiss Cheese Model”: accumulation of partly effective measures to obtain a maximal effect.
Some conclusions:
Peripheral antibodies elicited by SARS-CoV-2 vaccines applied > 6 months are waning. This is a normal phenomenon and does NOT imply that protection is waning too, since immune memory may remain longer than 6 months. The role of T cell immunity is not yet clear.
New variants are arising by “convergent” evolution. It is facilitated by the large pool of susceptible (unvaccinated or non-responsive) individuals worldwide. Obviously, the most “fit” variants with a combination of escape mutations may challenge the existing vaccines.
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