6 Oct 2021 Episode 180 : Efficacy of booster, discussion on side effects, overviews on efficacy of vaccines and follow-up on novel therapeutics

Dear colleagues,

As usually, some of you inspired me by sending interesting papers on various topics. I will try and provide some background and perspective….

How effective is the 3rd jab in the real world 60 + ?

Ep 180-1: Ber-On in NEJM reports on a population analysis during August on the effect of a third Pfizer vaccine in > 60 years old, who received the first two doses in  January or February and the third dose in July versus those who did not receive the booster.  The summary is shown in Table 1 p. 5 and Table 2 p. 6. It is very clear that at least 12 days after the booster, the chances on PCR confirmed infection and on severe illness were strongly diminished (factor 10-20) in all age groups over 60, irrespective of sex and social/ethnic group.  

How dangerous is vaccine-related vs COVID-related myocarditis?

Ep 180-2: A very critical report on “CIRM” (COVID-Related Injectables Myocarditis) in Current Problems in Cardiology (impact factor 5.2).   Based on an analysis of the U.S. Vaccine Adverse Events Reporting System (VAERS), the authors conclude that the risk on myocarditis, especially in young boys, was 19 times the expected background in the first 8 weeks of rolling out the mRNA vaccine.  Similar data have been reported before by CDC, but while previous reports claimed  myocarditis only led to short hospitalization, the authors of the present paper refer to 6 deaths of whom 2 in the teenage group. It is not clear to me whether those deaths are definitely related to mRNA vaccines…

The authors claim that “ It is vital to recall that children have a negligible risk for COVID-19 respiratory illness”, without analyzing in depth the risk/ benefit of vaccination versus disease in children. Moreover,  they do cast a lot of doubt on the mechanisms of action and safety of the existing COVID vaccines.

Ep 180-3 A: A study from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA (Pfizer) vaccine at 42 days after vaccination. Table 2 p. 1084  shows the main risks: lymphadenopathy > Herpes infections (recurrences?) >  vertigo and syncope > appendicitis > Bell’s palsy > paresthesia’s > myocarditis (RR = 2.7).   Fig 3 p. 1087 compares estimated risk ratios for adverse events after vaccination or SARS-CoV-2 infection: very serious complications such as kidney failure, thrombosis, myocardial infarction, lung embolism are much more common in COVID patients than vaccine recipients, hence could be prevented by vaccination, but the risk ratios for myocarditis in COVID and after vaccination actually overlap….

Ep 180-3 B: An MMWR report, analyzing 5000 cases of myocarditis, diagnosed  in US hospitals concludes: The risk for myocarditis among patients with COVID-19 during March 2020–January 2021 was nearly 16 times as high as the risk among patients without COVID-19, with the association between COVID-19 and myocarditis being most pronounced among children and older adults.  The Table p. 1230 indeed shows that the highest risk is in children < 16  (X 36) and  in elderly > 75 (X 31).

Ep 180-4: Another MMWR report of April 2021 analyzes how much COVID-19 contributed to mortality in the US in 2020.  As you can see in the Table p. 520, COVID mortality is rare in children: only 134 children below 15 years died of COVID (out of over 28,000 total deaths in children and out of over 337,000 total COVID deaths).

Follow-up on vaccine efficacy

Ep 180-5: A 6 months follow-up study on Pfizer by researchers from the company in NEJM confirms a persistently high, but slightly declining efficacy against COVID disease: over 90 % during 4 months and declining to 83.7 % thereafter (Fig 2 p. 9).  There was no age effect, but the teenagers and 75+ are a small minority in this study.   

My understanding is that this study was mainly done between Oct 2020 and April 2021, so the effect of delta is absent.  However, alpha, beta and gamma were present and there is no evidence that they have diminished the efficacy in South-Africa, nor Brazil or Argentina (Table 3 p. 10).

Ep 160-6: Is the phase 3 study Astra-Zeneca performed to obtain approval from CDC and is reported by researchers from the company, also in NEJM.  No clear data on duration of follow-up, but patients were recruited between end August 2020 and January 15 2021 in US, Peru and Chile, closing for analysis was on March 5 2021. In this trial 2 injections with a 4 weeks interval were applied (which is considered less favorable than the 3 months interval from the earlier published Brazil study)

• Overall efficacy against disease was 74 %, with even 83.5 % in 65+
• Completely protected against severe and critical disease (8 cases in placebo)
• Protected 64 % against infection (measured via Nucleoprotein Ab).

These data confirm earlier data, but do not provide long-term follow-up.  Based on these results I would think that Astra-Zeneca deserves the same status of approval as Janssen (see also next paper).  But AZ failed to get CDC approval.   

Ep 180-7: An interesting real world comparison of protective effect against hospitalization by the vaccines, available in the US during the first half of 2021.   Very didactic summaries Fig 1-2 p. 10-11.

• Effectiveness against hospitalization after full vaccination: Moderna 91 % > Pfizer 87 % > Janssen 68 % : effect of Janssen (single dose) comparable with mRNA single dose !
• Fully vaccinated elderly (> 85 yrs) and people with comorbidities very well protected.

Ep 180-8: A science journalist of Nature, commenting on the effect of vaccines on transmissibility (mainly based on a paper already discussed as Ep 179-7).  As a reminder  Pfizer cuts transmission more than Astra-Zeneca, Alpha is more susceptible to this effect than beta, but this transmission-reducing effect is also waning after several months….

Ep 180-9: Interesting preprint (medRxiv) analysis of breakthrough infections in San Francisco during 1st half of 2021.

• Fig 2 p. 14 shows clear predominance of gamma and delta strains in breakthrough infections, with “antibody-resistant associated mutations”, such as L452R/Q, E484K/Q, and/or F490S
• No clear association between breakthrough and mutations with increased infectivity.
• Moreover, viral load in breakthrough and unvaccinated infections were similar, suggesting equal infectivity (the latter in contrast with modeling, based on population data in UK  of 179-7) .

Progress in therapeutics

Ep 180-10: Favorable results of a single IV dose of Regeneron monoclonal antibody combination (active against variants of concern) in already infected outpatients.  Table 1 p. 7 shows a 70-80 % reduction of hospitalization and death in various subgroups (including previously infected subjects and those with co-morbidities).  Also 4 days quicker resolution of symptoms. Nice results, but I wonder about cost-benefit.  Maybe one should consider more fragile patients first?

Ep 180-11 A:  Merck now announces that a 5 days course of oral Molnupiravir in a similar patients group reduced hospitalization and death by 50 %.  These data were not yet published (even not in preprint) but the trial was interrupted by the monitoring board, because of the clearly beneficial effect.   

Ep 180-11 B:  Nature News and Views explaining that the effect of Molnupiravir on the RNA-dependent RNA polymerase is NOT chain termination (which is what Remdesivir does), but rather induction of a “catastrophic” waterfall of mutations (similar to the effect of Favipiravir).   

Some conclusions

1. A third jab with Pfizer shows a clear benefit against COVID in Israeli 60+ from 12 days after administration.  Follow-up was limited to 1 month.
2. Myocarditis is of concern after mRNA vaccination in teenagers, but COVID disease has many more complications in all age groups.
3. Confirmatory data on the order of efficacy of the 4 forerunner vaccines Moderna > Pfizer >> Jansen and Astra-Zeneca.
4. As expected, variants of concern, with antibody-resistant mutations are more frequent in breakthrough infections. Viral load was not different in unvaccinated and breakthrough infections.
5. The Regeneron anti-S monoclonals and the RdRpolymerase inhibitor Molnupiravir are useful to prevent hospitalization and death in already infected subjects.  Since they have a different mechanism of action, a combination of both could act synergistically.   

Best wishes,

Guido