30 April 2022 Episode 258: Various topics: Hepatitis; India; 3rd and 4th dose; BA.4 and BA.5

Sat, 04/30/2022 - 19:53

Episode 258:  Various topics: Hepatitis; India; 3rd and 4th dose; BA.4 and BA.5


Ep 258-1 = Ep 257-5, the review paper from Gastro-enterol Clin N Am, with a nice summary of hepatitis associated to COVID and Adenoviruses (the latter in tempore non suspect: July 2021). 

Herewith a summary slide on COVID hepatitis



With regard to Adenovirus, this review, just like Ep 257-3, does not mention serotype 41F, but rather the more common 1,2,3, 5 and 7 as culprit for hepatitis.  Most dangerous course is seen in Adeno-naïve (i.e. young children) with liver transplantation patients under immune suppression: very high fatality rate. A very typical histopathology is described focal coagulative necrosis, inflammation and  glassy intranuclear inclusions, staining positive for Adeno.


Ep 258-2: Lewnard Excess mortality in Chennai during first and second wave (until June 2021) Lancet Dec 2021:

  • Mortality excess of 5.2 per 1000 inhabitants (41 % increase over typical mortality) = more than twice that observed in US, Spain, Italy (= about 2 per 1000), despite the younger population in Chennai.
  • Official COVID death = 8167, total excess mortality about 23,000 → 3 fold underestimation.
  • As expected, clear increase with age, but remarkably,  a reduction in younger age groups.



Possible reasons for lower mortality in younger people:

    • Lockdown associated with lower transmission of other respiratory and GI infections?
    • Less road accidents, falls, occupational injuries?              


  • Higher mortality in lower socio-economic areas, especially during second peak:
    • Need to work outside even during lockdown?
    • Crowding result in higher transmission?
    • Lower access to health care

These Observations cast doubt on hygiene-related hypotheses of reduced SARS-CoV-2 severity in low-income and middle-income countries due to prevalent immunity from other infections.   


Par 1 Omicron BA-1 (and BA-2?)

Ep 258-3 : Malahe medRxiv 29 April 2022: Outcome of omicron in immunocompromised patients


Prospective study Dec 13 to Feb 2 = BA.1


114 pt with omicron infection included solid organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients on immunosuppressive therapy.  89 %  vaccinated 3X and 12 % 4th vaccine:

  • Hospital admission was frequent and the duration of symptoms often prolonged: 20% required hospital admission for a median duration of 11 days; 25% of patients had not yet fully recovered at the end of the follow-up period of 68 days after symptom onset.
  • Only 1 person died = much lower than previous VOC (14-20 %)
  • In particular lung– and kidney transplant recipients are likely to benefit from early treatment for COVID-19. In this study Sotrovimab was used, but it will be useless for BA.2 (and presumably also BA-2 derived VOC, such as BA-2.12.2, BA.4 and BA.5.


Ep 258-4:  Francesco Branda medRxiv 21 April 2022: favorable effect of 3rd dose on omicron in Italy (Nov 21- March 22: mainly BA-1)


Relative Risk at all ages vs non-vaccinated for hospitalization  0.16; 95% CI): 0.13-0.19),

admission to ICU (RR: 0.08; 95% CI: 0.06-0.09) and death (RR: 0.13; 95% CI: 0.10-0.16).


Ep 258-5: Caroza medRxiv 29 April Cumulative effect of prior infection and vaccination on protection against omicron in Quebec between 26 Dec 2021 and 12 March 2022 (largely BA.1)


  1. Prior infection alone had a waning protective effect ranging from 66 % at around 4 months to 35 % at around 10 months and < 30 % thereafter.  Remarkably: the more severe the prior infection, the greater the risk reduction: 8% (ASY), 43% (Sympt non-hosp) and 68% (hospitalized) (95%CI:51-80) for prior asymptomatic, symptomatic ambulatory or hospitalized infections.
  2. mRNA vaccine effectiveness against Omicron infection was consistently significantly higher among previously-infected vs. non-infected individuals: 1 dose 65 v 20 %; 2 doses 68 vs 42 % and 3 doses 83 vs 73 %


  1. The order of infection and vaccination doses is NOT important



  1. Prior infection alone: 81 %.  With 1 mRNA 86 %; 2 doses 94 %; 3 doses 97 %
  2. Two-dose effectiveness with prior-infection did not wane across 11 months and did not significantly differ from three-dose effectiveness (against hospitalization).

Conclusion: In the context of program goals to prevent severe outcomes and preserve healthcare system capacity, >2 doses of ancestral Wuhan-like vaccine may be of marginal incremental value to previously-infected individuals.


Ep 258-6: Arbel Nature Medicine April: Effectiveness of a second booster (4th dose) in 60 + Israeli.

Second booster (4th dose) vs 3 doses has a clearly protective effect:

  • Hospitalization: RR 0.36 (0.31-0.43)
  • Death: RR  0.22 (0.17 – 0.28)


Notes:  prior infection is not taken into account; follow-up is only 40 days.


A third and fourth dose has clear advantage, especially in older or immune depressed people and especially against severe outcome (hospitalization or death). The Canadian study, however, shows only a marginal effect of 3rd dose on hospitalization, if prior infection (hybrid immunity) at any time. Interestingly the protection of severe previous infection is much higher than after asymptomatic or mild-moderate infection. This study is on a general population and therefore it is not clear whether these conclusions also apply to older and/or immune compromised subsets.


BA-4 and BA-5

Ep 258-7: Tegally in medRxiv Emergence of BA4/5 in South-Africa in April 2022

  • The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493.
  • BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April.  
  • BA.4 and BA.5 have identical mutational patterns in the 5’ genome region (from ORF1ab to Envelope) yet exhibit genetic divergence in the 3’ region (from M to the 3’ genome end)      → Recombination event, with breakpoint between the E and M genes, prior to their emergence into the general population
  • Daily growth advantage versus BA.2 for BA.4 = 0.08 and for BA.5 = 0.012; which is similar to BA.2 advantage of 0.07 versus BA.1


Significance of mutations:

  • 69-70del: also in Alpha and BA.1 → S gene target failure with TaqPath
  • L452R: increased affinity for receptor; also in Delta, Kappa and Epsilon (L452Q in Lambda) and L452R/MQ in 4 BA.2 sublineages, including BA.2.12.1 in NY.
  • F486V: also seen in mink-derived viruses


Phylogeny of BA.2, BA.4 and BA.5: mutations that characterize the lineages are indicated on the branch at which each first emerged.


Amino acid mutations in the spike gene of the BA.4 and BA.5 lineages. Mutations that differ from BA.2 are denoted in red, including the wild-type amino acid at position Q493 (denoted by the red *).




Ep 258-8: Khan medRxiv: Escape of BA.4 and BA.5 from Omicron/BA.1 elicited immunity


Neutralization of BA.4 (a) or BA.5 (b) compared to BA.1 virus by immunity elicited through BA.1 infection in n=24 unvaccinated participants.

Neutralization of BA.4 (c) or BA.5 (d) compared to BA.1 virus by immunity elicited through BA.1 infection in n=15 participants vaccinated either with Pfizer BNT162b2 (n=8) or Johnson and Johnson Ad26.CoV2.S (n=7). Numbers are geometric mean titer (GMT) FRNT50. Dashed line is most concentrated plasma tested.

(e) Neutralization of BA.1, BA.4, and BA.5 in the n=15 Omicron/BA.1 infected vaccinated compared to the n=24 Omicron/BA.1 infected unvaccinated participants. Numbers are GMT FRNT50 and error bars are GMT 95% confidence intervals.


Conclusion: there is clear partial neutralization escape by BA.4 and BA.5 from immunity induced by BA.1, but this is less pronounced in vaccinated subjects. Hence BA.4 and BA.5 have potential to result in a new infection wave in BA.1 infected subjects. 


Question 1: Not clear whether that also applies to BA.2, since both BA.4 and BA.5 have only few additional S mutations, as compared to BA.2, while they differ more substantially from BA.1 !  


Question 2: Are these variants mild or severe? Difficult to say: during the last week of April, there is a steep rise of cases, but not (yet?) of hospitalizations in South-Africa….  





As you see, the story continues with new unknowns….


Best wishes,