3 July 2022 Episode 271: Fourth dose; variant specific booster, Bebtelovimab and BA.2.75

Sun, 07/03/2022 - 11:10

Episode 271: Fourth dose; variant specific booster, Bebtelovimab and BA.2.75

Dear colleagues,

In this episode I will summarize some evidence on the relative efficiency of a fourth dose with the ancestral mRNA vaccine, about the possible added value of a booster with a variant vaccine and explore the perspectives for new broad spectrum therapeutic monoclonal Bebtelovimab.  Finally, news on a new variant BA.2.75, based on information from Patrick Smits.  This will be the longest episode ever….

As an orientation for prevailing variants in the studies, a recent overview of the FT


PART 1 FOURTH DOSE (in elderly and Health Care Workers)


Ep 271-1: Gazit BMJ Retrospective study on 4th Pfizer vaccine in “seniors” (60 +)

  • Effectiveness against infection (omicron BA-1) wanes rather rapidly


  • Effectiveness against severe disease was more sustained


Limitations: short follow-up; no systematic testing and severe disease was rare (< 1%).


Ep 271-2: Cohen medRxiv April 2022: similar findings of reduced infection risk in HCW.  However, no severe disease or death in either 3- or 4 dose vaccinated individuals. Similar limitations as in elderly and possible confounder that more careful HCW choose to have the fourth dose. The main advantage in this population is avoidance of staff shortage by preventing sick leave.


Ep 271-3: Muhsen JAMA June 2022 Effectiveness of fourth dose in long-term care facilities

This is a prospective study amongst elderly residents (mean age = 80), 3rd and 4th receipents are well matched.


Relative protection of 4th versus 3rd dose against infection = only 34 %, against mild-moderate disease = 64 %; against hospitalization = 67 % and against COVID-related death = 72 %


Ep 271-4: Tall Bross-Nissimov CID June 2022 focuses on elderly hospitalized patients in Israel (mean age 80) with severe disease during the same BA-1 period (Jan-March 2022).   The following factors were independently associated  with “poor outcome (= mechanical ventilation or death).


The beneficial effect of a fourth dose of vaccine and Remdesivir treatment were expected, but the beneficial association with chronic lung disease remains unexplained.

Negative factors were male sex, dementia, renal failure and immune suppression. 

The lack of association with age may be because of the rather homogenous population.



Ep 271-5:  Grewal medRxiv 1 June  Fourth dose: test-negative control study in subjects over 60 in long-term care residents in Ontario (most were 80 +). 

  1. “Marginal” effectiveness (as compared to those who received 3rd dose long time ago)


This result seems less pronounced than in the Israeli study (e.g.  Ep 271-3)


  1.  Comparison between unvaccinated and dose 2,3,4




Clearly, a fourth dose provides additional protection against omicron.  I could not find whether age was an independent risk factor in this population.



  • A fourth dose seems indicated in elderly subjects, especially those in long-care residential facilities especially to reduce severe disease and mortality.
  • In HCW, a fourth dose is probably not life-saving, but could help to reduce absenteeism.

Note: All these data were gathered during the omicron BA-1 wave.  

Ep 266-11: Hachmann now in NEJM: (Relative) escape of BA.4/5 from both vaccination-induced and infection-induced immunity.



Ep 271-6: Chalkias medRxiv 25 June 2022: Moderna bivalent (Wuhan/Omicron BA.1) mRNA-1273.214 monovalent Wuhan-mRNA-1273 as a third dose compared:

  1. Higher neutralization against omicron BA.1, but titers lower than against D614G (= First European variant in 2020, immunologically similar to ancestral Wuhan strain).




  1. Also higher neutralization of BA.4/5, but those titers are even lower than against BA.1





Clear effect of “’hybrid immunity” in all cases

Ep 271-7: Pfizer Press release 25 June announces similar results (but no publication yet)

Given as a fourth dose:

Effect against omicron BA.1:

  • Monovalent omicron BA.1 vaccine at 30 μg and 60 μg dose : 13.5 and 19.6-fold increase in neutralizing geometric titers levels;
  • Bivalent vaccine candidate exhibited a 9.1 and 10.9-fold increase


Effect against BA.4/5:

  • Preliminary laboratory studies demonstrate both Omicron-adapted candidates neutralize Omicron BA.4 and BA.5 tough 3-fold lower than they do for BA.1


Clearly, these results of a 4th dose with Pfizer are similar as for 3rd dose Moderna, but unclear whether in the Pfizer trial prior infection was taken into account.

Ep 217-8: Launat medRxiv 27 May 2022 report on the effect of a recombinant spike protein, either based on D614G or Beta, as compared to wild-type Pfizer mRNA



Recombinant beta protein gives slightly higher neut titers against wild type, beta, delta and omicron (BA.1).

Interestingly, also induction of T cell responses slightly better by recombinant beta Spike


Unclear if some subjects had any previous SARS-CoV-2 infection.

Ep 271-9: Cao Nature 15 June BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection. 


  • Subjects, vaccinated with the inactivated CoronaVac (and no infection) have good Neut titers against D614G, but much weaker against all omicron variants
  • Subjects with BA.1 breakthrough infection develop hybrid immunity (higher neut) against BA.1; BA.2 and BA.3, but very weak responses against BA.2.12.1 and BA.4/5.

Further analysis showed that:

  • BA.1 infection induced mainly increase in wild-type responses
  • The mutations D405N, E452Q/R and F486V are escaped by BA.1-induced antibodies.


This situation is clearly different from infection with previous variants (alpha, beta, gamma, delta): they induced a broadening of the antibody responses; while omicron induces recall responses to ancestral epitopes (present in the vaccine).  This phenomenon is called “immune imprinting”: it deviates the immune responses away from the new virus and prevents robust immunity  

Ep 271-10: = Ep 266-6: Reynolds Science 14 June describes a complex effect of previous infection with various variants of concern (VOC) and triple vaccination on the T and B cell responses of HCW

  • As expected triple vaccination enhanced B and T cell immunity against previous  VOC, but responses against B.1.1.529 (omicron BA.1) spike was reduced
  • Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier VOC, but reduced nAb potency and T cell responses against B.1.1.529 itself.
  • Previous Wuhan Hu-1 infection abrogated T cell recognition and abrogated any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.
  • Similarly, infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529.


Despite the complexity, these data also point to the same phenomenon of “imprinting” instead of broadening of the immune responses by omicron.

Clearly, these findings are of concern with regard to the efficiency of omicron-based vaccines

Ep 271-11: According to Reuters FDA would prefer that BA.4/5 based boosters would be used in the Fall (instead of BA.1 boosters), “similar to influenza”.  It is not clear from the communication whether any immunogenicity or safety testing in humans would be required.  It seems also very unsure whether BA.4/5 will still be responsible for a Fall-Winter wave…..

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants


Ep 271-12: Westendorp Cell Rep May 2022:


  • In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant.


Data from Ep 271-9 (Cao)




  • The contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501, but LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y).


  • Interestingly, IC90 is always shown and not much higher than IC50, in contrast to e.g. S309 (Sotrovimab)



Ep 271-13: Ougan medRxiv 12 March 2022:   Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. 

Two trials are presented: a double blind placebo controlled study in mild-moderate infections with bebtelovimab (BEB alone or in combination  with Bamlavimab and Etesevimab) and an open label in high risk subjects, without placebo controls (mainly safety).  As can be seen in Table, the results, at first view are not spectacular: a slightly faster drop in viral load and in resolution of symptoms in the double blind study and no safety concerns.  No apparent influence on hospitalization or death, but there were very few events.



The important elements, however, are that:

  1. BEB remains fully active against life Omicron virus, while Bamlavimab + Etesivimab completely lose activity




  1. BEB has a very favorable pharmacokinetics, with serum concentrations > EC90 for more than 1 month




Ep 271-15:  THEREFORE BEB has received emergence use authorization in US for adult and pediatric patients:


  • with positive results of directSARS-CoV-2 viral testing, and
  • who are at high risk for progression to severeCOVID-19, including hospitalization or death, and
  • for whom alternate COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.


Ep 271-16:







BA2.75: the next wave? (entirely contributed by Patrick Smits)


BA.2.75 is worth monitoring, according to Tom Peacock, Eric Topola and Tom Wenseleer. It will have antibody escape that is similar to that for BA.4/5 with respect to current vaccine

The difference is that BA.4/5 have F486V mutation (which escapes antibodies from both current vaccine & BA.1 breakthrough), whereas BA.2.75 lacks F486V but has G446S (which escapes antibodies from current vaccine but less so from BA.1 breakthrough)




2 Key mutations BA.2.75


  1. G446S:


G446S will have less effect on antibodies of people with prior BA.1 breakthrough infection

Therefore, BA.2.75's antigenic advantage relative to BA.2 will be most pronounced in people who have NOT had BA.1 exposure.

We believe that next “mutation of concern” is most likely to fall in RBD 444-446, given that the only BA.4/5 effective broad and potent neutralizing antibody group (D2, including LY-CoV1404) is extremely susceptible to these residues.


  1. R493Q


G446S & F486V decrease ACE2 affinity of BA.2 (by -0.1 & -0.5 log10 Kd, respectively). But R493Q buffers these mutations by increasing ACE2 affinity by 1.1 log10 Kd

In general, ACE2-affinity enhancing mutations like R493Q (and previously N501Y) are often found with antibody-escape mutations.


Other mutations



  • K417E


  • W152R
    • (W152R) substitution suggests viral evolution to maintain effective binding to the ACE2 receptor (Kubik et al., 2021


  • F157L


  • I210V


  • G257S


  • D339H


  • N460K
    • In our deep mutational scanning of BA.2 RBD, N460K increases both ACE2 affinity (+0.2 log10 Kd) & RBD expression (a proxy for stability


Waar vinden we die mutaties nog:




Success of any variant also depends on inherent transmissibility, which is hard to measure experimentally & can only be estimated once there is sufficient epidemiological data to see how it fares in human population





  1. Fourth dose of standard mRNA vaccine was certainly useful to limit severe disease in elderly and absenteeism of HCW during the BA.1 wave. Clinical information on the effect of fourth dose on BA.4/5 has not yet been published, but the Hachman data show clear (relative) immune escape from both 3rd dose and from BA.1 or BA.2 infection-induced neutralizing antibodies.


  1. Omicron BA.1 specific vaccines (Moderna and Pfizer) as a third dose:  induce strong Ab neutralizing antibodies against D614G, but lower levels against omicron BA.1 and still lower levels against BA.4/5.  A booster with protein based beta variant seems less convincing.

It is presently unclear how that will translate clinically, but we can expect lower levels of protection against symptomatic infection and probably also less against severe disease?  Although, most probably, it will still be beneficial, it will become more difficult to convince the general public to get the next booster

  1.  While infection with previous variants (alpha, beta, gamma, delta) broadened the immune response and enhanced protection against the next variant, this favorable evolution is now being reversed: infection with omicron activates responses against previous variants, but fails to broaden the response. Hence protection against the next omicron variant is weak.  This is ab well-known phenomenon of “imprinting” that has also been observed with influenza.

→→ Could a combined Spike - Nucleoprotein based vaccine be a better option? ( to be explored in a next episode)  


  1. Bebtelovimab LY-CoV1404 is a human monoclonal Ab, derived from a convalescent COVID-19 patient, that has the broadest neutralizing activity until now, including BA.4/5 and BA.2.12.1.  Besides it’s breath, it is also very potent and, very interestingly, the EC90 is close to EC50, implying that it will have prolonged in vivo therapeutic concentrations.  Those characteristics are clearly distinct from S-309 or Sotroivimab that was originally derived from a SARS-CoV-1 patient: although very broad, the EC90 is much higher than EC50 and it is much less active against the latest omicron subvariants.

→ From a principal point, the good news is that the human immune system is capable of producing very broad and potent antibodies, also against omicron.

  1.   Will BA.2.75 fuel the next wave? Wait and see….


Best wishes,