20 March 2023 Episode 323 Follow-up on COVID vaccination and mAb therapy

Dear colleagues,

While COVID is around again in my well-vaccinated family, Ann (my wife) and I escaped once more (but for how long?).  An older (4 X vaccinated) colleague was hospitalized with a pulmonary embolism complication of the infection, but, fortunately, he fully recovered.  Various respiratory infections are still raging amongst children and elderly and whole families get ill from the viruses that their babies and toddlers catch in kindergarten.  You all see it around you, I’m sure.

Hopefully Spring will save us a bit from all these epidemics, but infectious diseases will continue to demand our attention…. Therefore, in this episode, I will follow up on COVID vaccination and therapy, mainly based on papers suggested by Patrick Smits and Frank Hulstaert.

Par 1 VACCINATION

1. 1. Clinical aspects: breakthrough infections with acute and long-term complications 

Ep 323-1: Hideki Tani bioRxiv 28 Feb 2023:  Neutralizing antibody levels and epidemiological information of patients with breakthrough COVID-19 infection in Toyama, Japan

44 specimens diagnosed with BTI COVID-19 after two or more vaccinations showed

• high inhibition of infection against the Wuhan strain and the Alpha and Delta.
• In contrast, almost no neutralizing activity was observed against the Omicron BA.1 variant.

(Half of the cases is shown.  The y-axis  is logarithmic)

Many cases without neutralizing activity or BTI were immunosuppressed individuals.

Thus, even after vaccination, sufficient precautions must be taken to prevent infection.

Ep 323-2: Eun Jung Jang  JAMA Open 10 March 2023: Effectiveness of hybrid BA.1/2 immunity on BA.5 symptomatic and (acute) severe infection in Korea

Vaccination alone has hardly any preventive effect on symptomatic BA.5 infection, while previous infection with BA.1/2 is highly protective.

3 or 4 vaccine doses alone are highly protective against critical BA.5 infection, with prior BA.1/2 infection showing no significant additional effect.

Ep 323-3: Eric Topol Ground Truth 4 March 2023 on excess cardiovascular burden after COVID and partial preventive effect of vaccination

The first four large matched cohort studies show that cardiovascular risk late after COVID is increased by 50 to 100 % in unvaccinated subjects

The latter two studies indicate that vaccination has a 50 % protective effect against long-term CV risk after breakthrough infection.

1. 2. Role of pre-existing immunity in response to mRNA vaccination

Ep 323-4: Tanushree Dangi Cell Reports Jan 2023:

In humans: higher antibody levels before boost with mRNA → lower fold increase in Ab after boost

In mice: adaptive transfer of human serum from vaccinated subjects accelerate the clearance of vaccine antigen via Fc-dependent mechanisms, limiting the amount of antigen available to prime B cell responses after mRNA boosters.

The human donor plasma has increasing Spike-specific IgG after each vaccination.

Transfer of this donor plasma to recipient mice, before they are mRNA vaccinated reduces the ensuing Spike IgG in those mice.  This is associated with lower antibody secreting plasma B cells (ASC) in the bone marrow  

In vitro experiment with human NK cell line indicates that Ab from vaccinated subjects can kill target cells that express the SARS-CoV-2 Spike via “Antibody-dependent cellular cytotoxicity” (ADCC).  These “target cells” are supposed to represent the “antigen-presenting cells”, loaded with Spike protein after uptake of mRNA.

1. 3.  Public health lessons learned from booster vaccination against a rapidly evolving virus

Ep 323-5: Paul Offit NEJM 8 Feb 2023: A cautionary tale about bivalent vaccines

The observation is that the bivalent vaccines have little (or no) advantage over monovalent vaccines to prevent symptomatic BTI, but that a booster mRNA (or previous infection) is still highly protective against severe disease.

Therefore:

Booster dosing is probably best reserved for the people most likely to need protection against severe disease — specifically, older adults, people with multiple coexisting conditions that put them at high risk for serious illness, and those who are immunocompromised.

In the meantime, I believe we should stop trying to prevent all symptomatic infections in healthy, young people by boosting them with vaccines containing mRNA from strains that might disappear a few months later.

Ep 323-6: Gretchen Vogel Science Insider 14 March: Questioning the vaccine mandates

Heidi Larson and other vaccine acceptance researchers …. emphasize that COVID-19 vaccines clearly prevent severe disease, but they worry maintaining the mandates could undermine future public health efforts. “Having to show these old vaccination proofs or certificates really doesn’t make sense, and it could cause harm, because people might lose trust in the competence of the organization,”  

Others say the conference vaccine requirements may be substituting for more effective ways to prevent spread of COVID-19.“If I were to see a meeting that had a vaccine requirement but then put everyone in the standard ballroom chairs shoulder to shoulder without a mask requirement, I might not consider that meeting seriously focused on COVID protection,” says University of Maryland School of Medicine epidemiologist Meagan Fitzpatrick, who models infectious disease transmission. “The vaccine requirement does not make it OK to drop all the other efforts that one might be able to deploy.”

Par 2 Is there still a place for mAb therapy in (rapidly changing) 0micron era?

2.1. Overview of present variants

Recent evolution in Belgium (Siensano 20 March2023): XBB.1.5 >> BQ ~ BA.2.75

2.2. In vitro neutralization data

Ep 323-7 Yunlong Cao bioRxiv 20 Oct 2022

Evusheld (COV-2 2196+2130 or Cilgavimab + Tixagevimab Astra Zeneca) is no longer active against BQ en XBB, has a limited effect against BA.2.75 (> 10X higher EC50), but activity against CH.1.1 of CA.2.  Presumably because of L452R mutation.

Sotrovimab (S309) has some effect against XBB, BA.2.75, but minimal not against BQ.1.1 

Bebtelovimab (LyCoV1404) is very active against BA.2, BA.2.75 en BA.5, maar fails against XBB, BQ and CH.1.1.

Ep 323-8: Akerman medRxiv 17 Jan 2023 shows similar results: Evusheld has no effect, but Sotrovimab has some effect on BA.2.75.2 and XBB, maar not on BQ.1.1 

2.3. Animal model In vivo

Ep 323-9: Jean-Sélim Driouich bioRxiv 4 Jan 2023  shows that 

Sotrovimab at the highest dose of 7 mg/kg is active to reduce the lung viral load against all Omicron variants tested (BA.1, BA.2 and BQ.1.1) similar as against the “ancestral B1 strain.

Evusheld is only tested against BQ.1.1 and shown inactive.

2.4. Clinical effects

Ep 323-10: Vishal Patel medRxiv 29 Nov 2022 Retrospective study during BA.2 and BA.5 period:  prophylactic therapy with Sotrovimab or Paxlovid has a benefit in high-risk patients, while Molnupiravir has a marginal effect.

These results are unexpectedly good in comparison with moderate neutralization in vitro.  This is tentatively explained by Fc-mediated effector functions such as ADCC (= antibody-dependent cytotoxicity) and ADCP (Ab-dependent phagocytosis)

Ep 323-11: Sridhara medRxiv 7 Dec 2022 Bebtelovimab has little effect during BA.2, BA.2.12 en BA.5 period (while these variants are sensitive in vitro).  

Ep 323-12: Danijela Miljanovic  Systematic review on therapeutic mAbs shows questionable effectiveness

Effect of various mAb (Evusheld, Bebtelovimab or Sotrovimab) on hospitalization avoidance

Effect of Sotrovimab on hospitalization

Clearly, although the overall effect, especially of Sotrovimab, seems beneficial, there is a lot of heterogeneity, most studies are small and often not well documented and controlled for bias.    

Ep 323-13: Evolving FDA recommendations

Ep 323-13-1: Advice against Evusheld (30 Jan 2023) 

Ep 323-13-2. Advice against Sotrovimab (4 April 2022)

Ep 323-13-3. Advice against Bebtelovimab (30 Nov 2022)

2.5. Very recent pharmacokinetic studies

Ep 323-14:  Eva Stadler et al. (of David Khoury's group) medRxiv 20 Dec 2023 model and extrapolate from in vitro to in vivo neutralization and show that you need a > 50 X of in vitro IC50 concentration for 50% in vivo protection. Of course, this model does not take into account other effects such as ADCC or ADCP.

Ep 323-15: Jaynier Moya medRxiv 7 Feb: Safety and pharmacokinetics of high dose (4X higher) Sotrovimab.

At 2000 (in stead of 500) milligram (mg): no safety issues, reaching a maximum serum concentration of 745 microgram/ml.  According to the in vitro neutralization data (Ep 323-7 and -8), 50 % neut is reached for 2/3 of the variants at concentration below 1000 nanogram/ml (= 1 microgram), while for BQ.1.1 the IC50 is at 5000 ng (= 5µg)/ml. 

Clearly, taking Ep 323-14 into account, a high Sotrovimab conc should be able to suppress the presently known variants in vivo at least partially….   

Provisional conclusion:

It is very questionable whether mAbs are still useful for the present variants. Sotrovimab may still have a beneficial effect in vivo, but this remains to be proven in prospective clinical trials. Unfortunately, SARS-CoV-2 is a “moving target”….  

Best wishes,

Guido