18 April 2022 Episode 255 Long COVID, hybrid immunity, breakthrough, children and escape from moAb

Mon, 04/18/2022 - 17:54

Dear colleagues,

After an Eastern break, herewith some new data of interest



First, please have a look at the 7 minutes video on brain complications of long COVID:


I was intrigued by the slide showing that vaccination in people with (cerebral) long COVID has a very uncertain effect and may even worsen the symptoms in 15 % (which would suggest an auto-immune pathogenesis). It is not clear where this figure comes from. As you know, there is quite some evidence that vaccination could prevent long COVID, but I was not aware of studies on vaccinating people who already suffer from long COVID.  There are a few:   

Ep 255-1:  Arnold medRxiv 2021 in UK reports on improvement of long-COVID in people vaccinated AFTER infection with either mRNA (Pfizer) or Adeno (Astra-Zeneca).  The figure does not show spectacular differences between vaccinated and unvaccinated, but the calculus seems positive: decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p=0.035).


Of note: the effect of vaccination on “brain fog” showed a rather mixed picture….

Ep 255-2: Viet-Thi Tran Res Square Feb 2022 in France shows rather similar results.  (For their scoring system see Ep 255-3).


Provisional conclusion: Vaccination (post infection) has no spectacular effect on long-COVID, but it is rather beneficial and there is no clear evidence that it would be deleterious. 


Hybrid immunity

Ep 255-4: Cele medRxiv April 2022 in South-Africa Beta infection + vaccination with Pfizer provides strong neutralizing antibodies against omicron BA.1 and BA.2

Beta infection alone elicited poor Omicron cross-neutralization, similar to what we previously found with BNT162b2 vaccination alone or in combination with ancestral or Delta virus infection.


However, only in vitro neut and no direct comparative data…. So not really clear if beta-infected + vaccinated subjects are really less susceptible to omicron infection.




Ep 255-5: Cerqueira-Silva medRxiv April 2022: During the Omicron-dominant period in Brazil, hybrid immunity offered high protection against severe illness and low protection against infection




A) Effectiveness of previous infection and hybrid immunity compared to unvaccinated individuals without previous infect.

B) Effectiveness of hybrid immunity compared to unvaccinated individuals with previous infection.

1st= First dose, 2nd= Second dose, Bt= Booster dose


Profile of breakthrough infections (BTI)


Ep 255-6: de Jesus medRxiv April 2022 on Brazilian BTI between half Jan and half Sept 2021 (gamma and delta VOC).


  1. The proportion of infected individuals who were vaccinated with BTI increases with time




  1. Breakthrough infections are often severe, especially fter CoronaVac or Astra-Zeneca than Janssen or Pfizer



Mostly older (> 60 years) man with co-morbidities (heart, diabetes).


Risk factors for unfavorable outcome: older age, respiratory compromise, inactivated virus vaccine immunization, and preexisting medical conditions.


Ep 255-7: Lang medRxiv April 2022: severe BTI in fully vaccinated PLWH in USA Jan-Dec 2021

  • No overall difference with matched HIV(-) controls
  • Risk factors amongst PLWH: being female, older, having a cancer diagnosis, and lower CD4 count, while previous COVID infection was relatively protective.





Ep 255-8:  Ayed medRxiv found no evidence of neurological development at 18 months in 40 neonates, who had been infected during their first months of life, despite the fact that over half had serious disease: 15 (37.5%) had a sepsis-like presentation, 5 (12.5%) had respiratory distress and 2 (5%) had a multisystem inflammatory syndrome in children (MIS-C)-like presentation


Ep 255-9:  Kaithan medRxiv April 2022 children with asymptomatic or symptomatic SARS-CoV-2 infection develop robust neutralizing antibodies that remain present longer than in adults but nevertheless wane in titer over time.





Emerging resistance to monoclonal Ab therapy or prophylaxis


As explained in Episode 253, the commercially available mAb, which were acting well against the early variants, lost activity against delta and even more against omicron.  In addition, there is also increasing evidence that resistance to originally sensitive SARS-CoV-2 can arise in treated patients, especially if the dose is low or the patient is immunocompromised.


ELI LILLY cocktail


Ep 255-10 : Focosi Emerg Infect Dis 2021: Induction of Q493R mutation in immunocompromised subject with resistance to both Bamlanivimab and Etesivimab.  Mechanism = increased affinity to ACE-2



Ep 255-11: Choudhary medRxiv Sept 2021: mono-therapy in regular (non-immunocompromised) patients with Bamlanivimab comparison in pre-VOC infected subjects low dose (700 mg) and high dose (7000 mg).  Clearly, low dose induced resistance-associated mutations and delayed clearance of virus 



REGENERON (Casirivimab + Imdevimab)


Ep 255-12:  Beddingfield medRxiv April 2022 Breakthrough gastro-intestinal COVID after Regeneron cocktail prophylaxis in one macaque.  The macaque had low respiratory viral load, but high GI load with 2 mutations in Spike and a loss of furin cleavage site deletion.  


SOTROVIMAB: (S309) is known to retain some activity against delta and omicron BA.1, but not BA.2.


Ep 255-13: Rocket NEJM April 2022: Sotrovimab therapy selects for Spike mutations in delta infections with persistent respiratory viral load.  (Four patients presumably immune-deficient)


Mutations at positions S:E340K/A/V and S:P337L/T (in receptor-binding site) have been associated with a reduction by a factor of 100 to 297 in neutralization by Sotrovimab





Ep 255-14: Destras medRxiv April 2022:  Sotrovimab rapidly induced mutations in Spike 337 and 340 of Omicron BA1, exclusively in immunocompromised patients.  SARS-CoV-2 remained present afterwards, except in one patient, who was also treated with convalescent plasma.  Hence Sotrovimab monotherapy should be avoided in these patients


Conclusion:  Prophylaxis and treatment of immunocompromised patients with monoclonal antibodies can easily induce resistance and therefore should be carefully monitored.  There is a clear risk of transmission and spread of resistant variants.


Best wishes,