3 March 2022 Episode 245 Looking back and forward on omicron and vaccination

Episode 245: Reflections on omicron and vaccination

Dear colleagues,

Today, most signals suggest that we are leaving the acute phase of the “Corona  crisis”, but yet another acute crisis of a totally different kind is rapidly unfolding in Eastern Europe…. Time to  wrap up COVID?  Maybe…

In any case, I choose a number of very recent papers (reviews and opinions) that look back and also look forward to give us a sense of where we are now.

In addition, I add some papers on decreased severity of omicron, on heterologous booster vaccination and on rapidly waning immunity in children after Pfizer vaccination in New York. 

Looking back

Ep 245-1: Birgit Prüss in Front Biosciences provides a nice overview on the characteristics of variants

Ep 245-2: Christopher Jung in J Virol provides a detailed analysis of the mutations outside and inside the Spike protein in BA.1 (referred to as 21K) and BA.2 (21L).  A detailed analysis of the (potential) functional significance of various non-Spike and Spike mutations is given.  One obvious conclusion is that there was little evolutionary pressure outside Spike and much more in Spike, presumably by partly immune hosts (people who were infected or vaccinated before), resulting in:

• Higher affinity for AC2, no need for TMPRSS2, resulting in endosomal entry.
• Escape from neutralizing antibodies, including most therapeutic monoclonals.
• Preserved sensitivity to antivirals, including Remdesivir, Molnupiravir, Paxlovid, but also soluble ACE-2.    

Ep 245-3: Qin Hong Nature 27 Feb 2022: Molecular basis of receptor binding and antibody neutralization of Omicron

In contrast to the S trimer of Delta/Beta/Kappa variants, the Omicron S-close and S-open structures appear more twisted/compact than their counterpart of the G614 strain.

This could be related to enhanced inter-protomer and S1-S2 interactions induced by unique Omicron substitutions (T547K, N856K, and N764K in SD1 and S2). Fig 1g

This closed state with all the receptor binding domain (RBDs) buried is possibly leading to conformational masking that may prevent antibody binding and neutralization at sites of receptor binding, similar to that described for HIV-1 envelope.  This could contribute to the striking immune evasion of the Omicron variant.

Substitutions on the receptor binding motif (RBM) of Omicron (especially Q493R, G496S, Q498R, S477N, and Y505H) result in formation of new salt bridges/H-bonds, and more complementary electrostatic surface properties (Fig. 2d-g), which together may compensate abolished original RBM-ACE2 interactions leading to enhanced interactions with ACE2 and potentially enhanced transmissibility of the Omicron variant.

Ep 245-4: Amber Dance Nature 3 March 2022 Omicron’s 4 questions scientists are racing to answer.

1. Why is it so transmissible: higher concentrations of viruses in the nose? See Ep 245-9.
2. Is it less severe: yes, especially in children less than five who had not been infected or vaccinated.  Why:
   • Less inflammation and damage to the lungs
   • No tendency to induce “syncytium” formation (= fusion of individual lung cells to non-functional “blobs”
3. What is the complete immune response to omicron
   • Although omicron is less sensitive to antibodies elicited by prior infection or vaccine
   • The T cell epitopes are conserved
   • And, according to some, omicron has less ability to escape from type 1 IFN
4. What comes next? Certainly not clear
   • Attenuation to upper respiratory virus (adaptation to grow at 33°C)?
   • Further evolution in animal species?
   • Acquisition of novel binding/entry pathways: e.g. via heparan sulphate at cell surface?
   • Escape not only from antibodies, but also from antivirals?

Ep 245-5A: Saima May Sidik Nature Briefing 25 Feb 2022: Had omicron (BA.1), unlikely to catch its rising variant (BA.2)?

There have been contradictory claims about the pathogenicity and escape characteristics of BA.2 versus or after BA.1.  See Ep 242 and 244:

1. BA.2 has taken over the BA.1 epidemic in South-Africa, Denmark and England. BA.2 has indeed a higher replicative capacity than BA.1 (and delta).
2. Ep 242-2 In vitro, BA.2 seems to grow better in nasal epithelial cells than BA.1, but in the hamster model it is also more pathogenic than BA.1. In fact, it produces similar weight loss, infection in the lung, alveolar damage and decrease of oxygen saturation as the D614G strain, which was responsible for the first worldwide pandemic wave.
3. Ep 242-5 The detailed “real world” household transmission studies provide a mixed picture: whereas susceptibility to infection by BA.2 is 2-3 times increased as compared to BA.1, regardless of vaccination status, transmissibility is only increased from unvaccinated, but actually relatively decreased from vaccinated subjects.  In any case, in Denmark, BA.2 has taken over BA.1.
4. However, according to Ep 242-3, BA.1 infection induces antibodies, capable to neutralize BA.2, probably explaining why the (relative) take-over by BA.2 in South-Africa, Denmark and England did NOT result in a new (absolute) rise in cases, but, on the contrary occurred during a decline, while anti-COVID measures were relaxed.       
5. Ep 244-13: Stegger medRxiv 22 Feb 2022 Reinfection with BA.2 after BA.1

Within 1.8 million infections between Nov 22 and Feb 11 in Denmark, there were 187 reinfections (> 20 days and <60 after first infection).

Clearly, reinfection over short time frame is rare (187/1,800,000). 

• • 47 cases of reinfection with the same variant (17 BA.A + 30 delta)
  • 47 cases of BA.2 after BA.1: these were usually mild infections in young (mean 16 years) unvaccinated (68%) subjects.

CONCLUSION: 

“It’s predominantly young, unvaccinated persons where we see this reinfection with BA.2.

It kind of indicates that vaccination does give you some protection”

Taken together the results suggest that BA.2 is unlikely to cause a major wave of infections in communities that have experienced a BA.1 wave.

Note: Ep 245-5 B:  According to the “genomic surveillance” also in Belgium, BA.2 is “taking over” the epidemic, while the total number of new cases continues to decrease see Ep 245-6 and the positivity rate remains stable.

Looking forward

Ep 245-6: Denis Normile predicts that China will gradually loosen its “zero COVID” strategy, because it becomes too worrisome.  The situation in Hong Kong may be one of the reasons: while the epidemic was kept under control until very recently, cases are going up very steeply 

Ep 245-7: Heidi Ledford Nature Briefing 28 Feb 2022: Three questions about the next variant

1. When will a new variant arise?   Probably every few months, but we might not detect it immediately, since testing and sequencing efforts are declining….
2. Will it be less severe? “ There is no guarantee that the next dominant variant will sprout from the ‘mild’ Omicron branch of the SARS-CoV-2 family tree. “It is possible that a later variant may be back to a Delta or Alpha lineage, with sufficient immune evasion to sweep Omicron away,” says Rambaut, who studies viral evolution at the University of Edinburgh.
3. Will vaccines protect against emerging variants?

Several lines of evidence point to importance of repeated exposure to either vaccination or infection to build up immunity.  The importance of T cells is emphasized again, but next variants could escape from that immunity as well.

Ultimately, the data continue to point to the importance of vaccination, says Burgers (University of Cape Town). “We know that vaccines shore up our immunity and that immunity will be cross-reactive, when it comes to T cells, with another variant,”

Ep 245-8:  Sarun Charumilind McKisney March 2022: When will the COVID pandemic end?

A nice overview, with highlights by Patrick Smits.  Easy to read. Some didactic figures and tables

Viral load

Ep 245-9: Salvagno J Infect 22 Feb 2022: SARS-CoV-2 Omicron infection is associated with high

nasopharyngeal viral load.

Retrospective study, comparing NP load in Jan 2021 and Jan 2022: Ct value significantly lower during omicron period, thus viral load is higher.

Two papers on disease severity

Ep 245-10: Jassat medRxiv 23 Feb 2022 on clinical severity in South-Africa across the four waves

Omicron is clearly associated with lower severity, but other factors are important as well:

• As generally known: increasing age, male sex, co-morbidities
• But also: all provinces outside Western Cape.

Ep 245-11: Birol Ilter in Turkey shows in a small retrospective study during Jan 2022 (omicron), that disease severity in unvaccinated pregnant women is more prevalent (9.6 %) than in vaccinated ones (0 %): mainly need for  oxygen support… However, unclear whether this was based on objective criteria such as arterial oxygen saturation….

Two papers on heterologous 3rd boost

Ep 245-12: Heinzel medRxiv 22 Feb:  2022 Heterologous (Janssen as 3rd dose) superior to 3rd mRNA in kidney transplant patients (under immune suppressive therapy -see Table 1)

• Similar seroconversion rate (45-50 %) and CD4 as well as CD8 T cell responses
• Higher antibody levels in vector group at 3 months after booster

Ep 245-13: Zhuxiang Zhao Emerg Microb Infect Feb 2022 showing that the use of recombinant subunit receptor binding domain protein vaccine (Zifivax see Ep 237-12) as 3rd dose after 2 doses of inactivated vaccine (I-I-S) is superior to using inactivated vaccine again as 3rd dose (I-I-I).

• Much better neut Ab against several VOC

• As expected titers against omicron lower

• Unfortunately neut titers wane over 3 months, but much more against omicron and especially when inactivated vaccine is used as 3rd dose

Vaccine effectiveness (VE) in children  

Ep 245-14: Dorabawilla medRxiv 28 Feb 2022: Rapidly decreasing VE in children in New York during omicron wave.

Conclusions by the authors:

In the Omicron era, the effectiveness against cases (infection) of BNT162b2 declined rapidly for children, particularly those 5-11 years. See Fig 1-2.

However, vaccination of children 5-11 years was protective against severe disease (See Table) and is recommended.

These results highlight the potential need to study alternative vaccine dosing for children and the continued importance layered protections, including mask wearing, to prevent infection and transmission.

Comments by colleague Pierre Vandamme

Not so surprising: when I read  the paper, I learn 3 things:

1. In the adolescents we see the same as in the adults, decreasing efficacy against symptomatic infections. An extra reason to use a booster as far as omikron is concerned.

2. In the kids, the decrease in efficacy against symptom infections occurs even faster, and can therefore be vaccine dose related – more ideal schedule with a higher dose and/or booster to be investigated, but the MSS is sufficient for future variants… progressing insight

3. Still some limitations in the study, with broad confidence intervals.

Best wishes,

Guido