8 August Episode 160 Colombian versus other variants, future scenarios and side effects of vaccines.

Dear colleagues,

Besides the medal race in Tokyo, the many climate catastrophes over the world, including Belgium, last week was marked by an outbreak of the Colombian variant in fully Pfizer vaccinated elderly in Zaventem (where Brussels Airport is located).  I try to put this case into perspective.

I also received from colleagues two very interesting documents from SAGE and Paul Ehrlich that I want to share and summarize.

Ep 160-1: Marc Van Ranst comments on the “Zaventem outbreak”.  This elderly population is  very vulnerable: they most probably never developed high quality/quantity of protective Ab or lost them very rapidly.  This was indeed expected, based on papers Ep 149-14 A and B.

Ep 160-2: Comparison of the main VOC and the “Colombian” B.1.621. Clearly, this variant shares:  

• E484K with beta, gamma and delta
• N501Y with alpha, beta and gamma
• P681H with alpha (delta has P681R)

The former two mutations are in the receptor-binding domain and may contribute to immune escape and/or higher affinity to ACE2.  The latter is at the S1/S2 site, hence may influence fusion efficiency

On p. 2 also a nice overview of the evolution of variants In Belgium

Ep 160-3: A description from Colombia, where the variant emerged in January and got “fixed” in Northern departments, but co-circulated with other variants.  Nevertheless, it temporarily dominated Magdalena and Atlantico.  See Fig 1 p. 13.

Ep 160-4:  Very short description of a 7-person cluster, infected with B.1.621 in Brescia (Northern Italy).  Presumably unvaccinated subjects and with “unspecified symptoms”.  The authors show that this variant has a 2-fold reduced sensitivity to sera from Pfizer-vaccinated individuals. 

Ep 160-5: Although it is difficult to interpret such an isolated result, we can put it in perspective with a recent overview of 36 studies on neutralization sensitivity of VOC to sera from mRNA vaccinated individuals. As can be seen in Table 1, the reduction for alpha is about 2-fold, in Table 2 on beta it is between 3 and 40-fold; in Table 3 on gamma between 2 and 6-fold and in Table 4 on delta between 1.5 and 8 fold. As discussed before, these assays are not standardized enough to directly quantitatively compare all these results, but the trend is clear: the alpha and Colombian variant lose only about 2 fold, while beta and gamma tend to be more resistant to neutralization after mRNA vaccination, hence more likely to “break through”.   

Ep 160-6:  Looking for more recent data on Colombia, I only found this paper, describing lineages coming over from Venezuela.  There is no mention of B.1.621 and also not of the gamma and delta variants.  It looks, however, that genotyping is done only sporadically….

On this website https://cov-lineages.org/lineage.html?lineage=B.1.621  you can see that this variant has a limited distribution in the North-Eastern part of South-America, Mexico, US and Western Europe.

Conclusion:   B.1.621 (Colombian) is a variant that shares some characteristics with the alpha-to-delta VOC, but it is not of major concern.  The slight reduction in sensitivity to mRNA vaccine-induced neutralization is not sufficient for any “vaccine resistance”, unless, of course, the vaccinated people make very weak Ab responses in the first place.

Ep 160-7: Darren et al discuss the evolution, seen in the N501Y lineages (alpha, beta, gamma) and non-N501Y lineages, the most important of which is delta.  They observe over 60 genomic sites where “signature” and “convergent” mutations occur: 24 in S, 21 in the replicase complex (ORF1), 11 in N and 7 in other non-structural proteins (see Fig 3 p. 10).  These mutations contribute to increased affinity for ACE2, increased transmissibility,  better replication, interference with natural immunity (e.g. type 1 interferon), increased virulence and/or escape from neutralizing antibodies.

These authors foresee that recombination of variants, under pressure of increasing infection- or vaccination-induced immunity, could give rise to even more transmissible and virulent viruses.   In fact, they propose to mimic this evolution by culturing variant viruses in the presence of neutralizing antibodies to force this type of recombination to occur in cell culture and thus potentially predict which new variants might arise in human populations.  Although this type of in vitro evolution is lacking some crucial elements such as airborne transmission, this exercise is of obvious interest for vaccine developers.

Ep 160-8: The Scientific Advisory Group For Emergencies (SAGE) in the UK builds on this and other  hypotheses to depict four possible scenarios:

1. The worst case: SARS-CoV-2 becomes highly transmissible and as deadly as SARS-CoV or MERS.   What can we do to prevent or contain it?

• Consider vaccine booster doses to maintain protection against severe disease.
• Reduce transmission of SARS-CoV-2 with non-pharmacological interventions
• Minimise introduction of new variants from other territories to reduce risk of recombination
• Targeted surveillance for reverse zoonoses, and if necessary, consider animal vaccination, slaughter, or isolation policies.
• Continue to monitor disease severity associated with variants (to identify changes in phenotype).
• Continue to develop improved prophylactic and therapeutic drugs for SARS-CoV-2 and disease symptoms.

2.  A variant that evades current vaccines: To do:

• Monitor antigenic variants and update candidate vaccines to cover antigenic escape variants.
• Conduct clinical trials of re-vaccination with antigenically distant vaccines
• Consider clinical trials of multi-valent vaccines.
• Re-vaccinate vulnerable age groups at regular periods with updated vaccines to the dominant antigenic drift variants to increase an individual’s immunological landscape to SARS-CoV-2 variants.

• Reduce transmission of SARS-CoV-2 (to reduce risk of point mutations, recombination).
• Minimise introduction of new variants from other territories (to reduce risk of recombination).
• Monitor reverse zoonoses and if necessary, consider animal vaccination, slaughter, or isolation.
• Continue to develop improved prophylactic and therapeutic drugs for SARS-CoV-2.

3. Emergence of a drug resistant variant after anti-viral strategies

• Only use antiviral combination therapy, using ≥2 drugs with different targets or mechanism of action.
• Preserve antiviral use for an emergency in which a SARS-CoV-2 variant is more severe, and a matched vaccine is unavailable and takes time to develop.
• Use antivirals cautiously in immunocompromised people in whom long term evolution can happen – monitor for treatment failure and resistance, minimise risk of onwards transmission of resistant variants using appropriate PPE.

4. SARS-CoV-2 follows an evolutionary trajectory with decreased virulence = best case scenario

Unlikely in the short term, realistic possibility in the long term.

General considerations for further reducing the impacts of variants:

• Vaccinate the world
• Develop vaccines inducing mucosal immunity
• Careful use of antivirals (to reduce development of resistance)
• Genomic and phenotypic surveillance
• “Onshoring” of capacity to produce equipment, masks, drugs, vaccines….

Ep 160-9: Paul Ehrlich Institute on side effects of first 50 million COVID vaccinations in Germany

(37 million Pfizer; 4 million Moderna; 9 million Astra-Zeneca and 472,000 Janssen)

First: It should be noted that adverse reactions are reported in the temporal, but not necessarily in the causal, connection with a vaccination. (see Metodik p. 32).

Suspected serious side effects (“Verdachtsfälle von schwerwiegende Nebenwirkungen”) Table 2 p. 8:

Pfizer and Moderna: each 0.1/1000

Vaxzevria: 0.4/1000

Janssen: 0.03/1000

Unfortunately, I could not find a clear definition of “serious side effects”, but Table 9 p. 23 provides an observed versus expected analysis of  7 serious events: myocardial infarction, myocarditis, thrombocytopenia; encephalitis; facial paresis, Guillain-Barré Syndrome and arthritis. 

In fact, only thrombocytopenia and Guillain Barre syndrome after Vaxzevria were elevated.  

More detailed descriptions in the text.

With regard to anaphylaxis: there were 293 reports, of which 175 with clear symptoms.

- Interestingly, only 81 occurred within 15 minutes and 109 within 30 minutes.

- Apparently all cases evolved finally well.

- Incidence (see Table 8 p. 22):

Pfizer: 130/ 37 million = 0.35 per 1000;

Moderna: 7/ 4 million = 0.15 per 1000

Vaxzevria : 33/ 9 million = 0.36 per 1000

                Janssen: 0/472,000 = 0 per 1000

With regard to mortality (“Todesfälle”), I like to quote the text p. 8 (in translation):

To Paul Ehrlich Institute 873 deaths have been reported (0.0024% of the vaccinated people) at different times after the vaccination in people between the ages of 24 and 102 years. The median age was 81 years and the mean age was 77 years

The vast majority of the deceased had multiple previous illnesses, such as B. carcinoma, renal insufficiency, heart disease and arteriosclerotic changes, which were presumably the cause of death. A younger patient presumably died after vaccination with Comirnaty as a result of drug use.

Twenty-one patients vaccinated with Vaxzezvria, died as a consequence of thrombotic events.  

Some General Conclusions:

1. The Colombian variant is NOT of major concern.

2. The convergent evolution of variants of concern does NOT imply that the virus has no more “cards to play”.  More transmissible and virulent recombinants may arise.  We need to prepare for that possibility.

3. Vaccination in Germany was very safe. 

Best wishes,

Guido