3 Sept 2022 Episode 285: Further data and discussion on protection by infection and bivalent vaccines in in the omicron era.

Sat, 09/03/2022 - 15:09

The popular impression is that, since the arrival of omicron, a previous infection or vaccination offers little protection against the newer omicron subvariants, but data from several parts of the world show the opposite.

The US and European authorities have approved bivalent vaccines, but there are remarkable differences.    

Par 1 Evidence of protection by previous infections and vaccination in omicron and particularly BA.5 era

  • The epidemiological trends of disease severity in South-Africa are described: increasing from Wuhan to delta and decreasing during successive omicron waves.
  • Reinfections
    • in unvaccinated subjects in Qatar: high with BA.1/2, but low with BA.4/5
    • in vaccinated subjects of Portugal:  previous BA.1/2 protects against breakthrough with BA.5.
  • Similar data from USA and Denmark:
    • During first omicron wave, there was an increase in reinfections and vaccine breakthrough infections:
    • Nevertheless: there is a clear-cut protective effect of natural and vaccine immunity, with prior infection providing ~6 months of protection from reinfection.
  • Third and fourth dose of mRNA vaccines have a clear (> 50 %) incremental protective effect against severe disease in England
  • Also clear-cut reduction of omicron infectiousness by previous infection and/or vaccination in USA

Ep 285-1 : Waasila Jassat medRxiv 25 Aug 2022 on Very nice data on trends in South-Africa.

Number of infections: increased from Wuhan to Omicron BA.1/2, but decreased in BA.4/5


Hospital admission incidence risk and in-hospital mortality

  • increased progressively first three waves (Wuhan-Beta-Delta)
  • decreased in the BA.1/BA.2 wave and declined further in the fifth Omicron BA.4/BA.5 wave.

Mortality risk:

  • Increased with age, male sex, co-morbidities.
  • Higher in public sector and certain provinces.
  • Higher in Delta and Omicron BA.1/2 as compared to BA.4/5
  • Lower in those with natural infection and vaccination, declining further as the number of vaccine doses increased. 


Ep 285-2: Chemaitelli medRxiv 24 Aug 22  Immune protection against SARS-CoV-2 re-reinfection and immune imprinting in Qatar


Matched retrospective cohort of non-vaccinated individuals.


Adjusted hazard ratio (aHR) for infection was 0.52, comparing reinfection cohort with primary-infection cohort:

  • aHR 0.59 if primary infection was Wuhan or Alpha
  • aHR 0.92 during omicron BA.1/2: clearly MORE breakthrough
  • aHR 0.46 during omicron BA.4/5: clearly LESS breakthrough


No evidence that immune imprinting compromises protection against Omicron subvariants.


However: having two infections, one with a pre-Omicron variant followed by one with an Omicron subvariant,

→ stronger protection against Omicron-subvariant reinfection than only one infection with an Omicron subvariant.


Ep 285-3: Malato NEJM 31 Aug 2022 Risk of BA.5 in previously infected and vaccinated subjects according to variant in Portugal.


In a highly vaccinated population (98 %), breakthrough infections with BA.5 were less likely among persons with a previous SARS-CoV-2 infection  than among uninfected persons.

- especially for previous BA.1 or BA.2 infection,


This is in contrast with public perception.  The paradox can be explained by the height of the omicron BA.1/2 wave, hence, even with a relatively better protection, the absolute number of BA.5 breakthrough remains high.


The protection afforded by BA.1 against infection by the BA.5 subvariant is critical because adapted vaccines now approved by EMA are based on BA.1 (see Par 2).



Ep 285-4: Mihika Nadig medRxiv 24 Aug 22: Recent SARS-CoV-2 infection reduces risk on omicron infection and hospitalization in USA


During omicron wave, there was an increase in reinfections and vaccine breakthrough infections:  


Nevertheless: there is a clear-cut protective effect of natural and vaccine immunity, with prior infection providing ~6 months of protection from reinfection.


Fig 2 a: Relative risk of (any) reinfection increased during omicron

Fig 2 b: Relative risk of omicron reinfection decreased after a recent prior infection


Ep 285-5: Holm Hansen SSRN Aug 2022 Risk of BA.5 reinfection in Denmark 


  • High protection against BA.5 from prior omicron infection in triple-vaccinated individuals,
  • Similar vaccine effectiveness for BA.5 infection as currently for BA.2.


Remarkably: BA.5 infection was associated with an increased risk of hospitalization in an analysis adjusted

for covariates, which needs confirmation and continued surveillance as hospitalizations were low and stable during the study period.


Ep 285-6:  Kirsebom medRxiv 1 Sept 22 Effectiveness of vaccines against severe disease with BA.4-5 in England.  


Incremental VE was estimated in those vaccinated with either a third or fourth dose as compared to individuals with waned immunity who had received their second dose at least 25 weeks prior.


Incremental VE was 56.8% for BA.4;  59.9% for BA.5 and 52.4% for BA.2 at 2 to 14 weeks after a third or fourth dose


Ep 285-7: Sophie Tan medRxiv 9 Aug 22 Infectiousness of breakthrough and reinfection of omicron subvariant USA.


SARS-CoV-2 surveillance in Californian prisons: index case’s risk of transmitting to close contacts is reduced by:

  • 24% (9-37%) after vaccination
  • 21% (4-36%) after previous infection
  • 41% (23-54%) after both (= hybrid immunity)


Par 2 Update on bivalent mRNA vaccines


2.1 Evidence provided by the companies


Ep 285-8 : Pfizer


  1. Human data on improved neutralization titers obtained with bivalent Wuhan + BA.1 vaccine (OMI BA.1)


Bivalent vaccine (OMI BA.1) as compared to original vaccine (BNT162b2) as fourth dose (after 3 doses of BNT162b2) induces superior neut titers against BA.1


Also very good, but lower titers against BA.4/5


  1. For Omicron BA.4/5 vaccine only mouse data: both monovalent and bivalent → consistent high neut across variants 


Ep 285-9: Moderna


  1. Omicron BA.1 vaccine = bivalent (mRNA-1273.214) as fourth dose induces higher neut in humans than original (mRNA-1273)



Also high neut titers against BA.4/5


  1. Both bivalent omicron vaccines (BA.1 = mRNA-1273.214; BA.4/5 = mRNA-1272.222) protect better than the original against lung infection in mice 


Conclusion: Pfizer and Moderna provide very similar data:

  • Bivalent BA.1 vaccine as 4th dose induces better neut against BA.1 and BA.4/5 virus in humans = clinal data, without efficacy (no data on prevention of infection)
  • Bivalent BA.4/5 as 4th dose induces excellent neut against BA.4/5 in mice = preclinical data


2.2 Decisions by European and US authorities (EMA and FDA)


Ep 285-10:  FDA on 31 Aug goes for bivalent BA.4/5 as booster and advices against monovalent original vaccine


Ep 285-11: EMA on 1 Sept goes for bivalent BA.1.  

  • The original versions can still be used, especially as first doses. 
  • Member States can decide who will receive which vaccine.
  • BA.4/5 vaccines  are under review


2.3  CDC guidelines 1 Sept


Ep 285-12: Very comprehensive and clear recommendations


  1. Adapted COVID vaccination for people > 12


  1. Pre-exposure prophylaxis with Evusheld


  1. Co-administration of other recommended vaccines (including Influenza) is encouraged.




Bivalent vaccines will now be used in US (BA.5) and Europe (BA.1). 

Modeling by Khoury (see Ep 284-13) shows that the advantage of an adapted versus the original booster vaccine remains limited, but depends on several factors, including the time since last booster.   Getting any booster is more important than which booster.  

The main unknown factor is which variant will circulate in the next Fall-Winter season.  


Best wishes,