15 Sept 2021 Episode 173 : Update on vaccines and antibodies

Dear colleagues,

A lighter episode on mRNA vaccines in adolescents, side effects and antibody therapy

mRNA vaccines in adolescents

Ep 173-0: the long story on how mRNA vaccines have been developed over the last decades.  The crucial elements of success are:  

• the “mRNA modification”: replacing uridine by pseudo-uridine, to decrease the triggering of Toll-receptors and the induction of too much, too early type1 IFN (which would stimulate intracellular RNAses and reduces immune responses)
• the composition of the lipo-nanoparticles to protect the mRNA from ubiquitous extracellular RNAses, to fuse with the cell membrane and deliver the intact mRNA to the cytoplasm for translation by ribosomes.

Ep 173-1: A reminder of the Frenk paper in NEJM (May) on phase 3 of BNT162b2 (Pfizer) in> 1100  12-15 years old between Oct 2020 and Jan 2021

• Quite some side effects, but comparable to 16-25 yrs and acceptable.
• RBD-specific and Neut antibody titers slightly higher than in 16-25 yrs old
• 100 % efficacious: 0 infections in vaccine vs 16 in placebo.

Ep 173-2: Kashif Ali in NEJM Aug on phasec 2-3 of mRNA1273 (Moderna) in almost 2500  12-15 yrs old between Dec 2020 and Feb 2021

• Also quite some but acceptable side effects.
• Also slightly better Ab titers than in young adults.  
• Also 100 % efficacious (0 infection in vaccine vs 4 in placebo groups)  

Ep 173-3: Large matched controlled study on side effects of Pfizer vaccine in about 900,000 US vaccinees.

Main serious side effects RR > 1.1):

• Appendicitis  
• Bell’s Palsy
• Lymphadenpathy
• Herpes simplex and zoster
• Myocarditis, pericarditis,
• Paresthesia’s, syncope, vertigo
• Uveitis

Comment: vaccines are clearly beneficial as compared to side effects of COVID.

Ep 173-4: Review and recommendations on serious anaphylaxis after COVID vaccines:

• The incidence of anaphylaxis is 7.91 cases per million
• Testing for PEG (poly-ethylene glycol) allergy has a low sensitivity, but high specificity.  
• Vaccination is recommended if no proof of severe allergy to either SARS-CoV-2 vaccine or constituents such as PEG of polysorbate.

Ep 173-5: Risk benefit of vaccination for 12-17 years old in UK:

• Against hospitalization: remains positive unless virus incidence would drop below 30/100,000 (while presently > 400/100,000).  Main reason for (short) hospitalization after vaccination = myocarditis.
• Against death and long COVID: remains positive at any SARS-CoV-2 infection rate, since no deaths or long COVID after vaccination.  

Antibody therapy

Ep 173-6: Result “Covid-19 Convalescent Plasma in Outpatients” study: administration of high-tittered neutralizing Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression.  

Comment: So, again a study that shows convalescent plasma to be ineffective.

Seems quite in contrast to monoclonal antibodies e.g. REGN COV 2 (Regeneron), BUT…..

Ep 173-7: Weinreich in NEJM (Jan 2021):  REGN COV2, a combination of 2 anti-Spike human neutralizing monoclonal antibodies in outpatients with a recently confirmed infection (< 72 hrs) and onset of symptoms (< 7 days).

• Clear-cut effect on lowering viral load, but much more pronounced if initial viral load was high (> 105 logs) and no endogenous antibodies yet (See Fig 2 p. 248)
• Clinical effect: 50 % reduction in “seeking medical attention”, but overall only 12/275 needed medical assistance.

Comment: clearly, this was not a high risk population.  Therefore “real world data” are needed.

Ep 173-8 A: Verderese in CID (June 2021): Mild/moderate patients receiving NmAb had significantly:

- lower hospitalization rates (5.8% vs 11.4%,),

- shorter length of stay if hospitalized (mean, 5.2 vs 7.4 days),

- fewer Emergency Department visits within 30 days post-index (8.1% vs 12.3%,) than controls

 But no difference in mortality: 4/707 in the treatment group vs 24/1709 in controls.

Comment: a retrospective study, with two different antibody cocktails and with “historic” controls.

Ep 173-8 B: Ash in Am J Emerg Med (July 2021): a “convenience sample” of 68 mild-moderate COVID patients with a median age of 69,  all treated with REGN COV2 (hence no controls).  The findings:

Following REGN-COV2 infusion, few patients under 65 re-presented to the emergency department.

However, a large number of patients aged over 65 years re-presented to the ED following infusion.

Comment: Not terribly convincing, but potentially  pointing to an age-effect….

Ep 173-9: Prophylatic use of REGN COV2 in household contacts:

Symptomatic SARS-CoV-2 infection        in 11/753 (1.5 %) participants of  REGEN-COV group

in 59 /752 (7.8 % ) of the placebo group  → > 80 % effect

REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%).

Among symptomatic infected participants,

• median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, resp),
• duration of high viral load (>104 copies per milliliter) was shorter (0.4 wks and 1.3 wks, resp.)

Comment:  at first view, these prophylactic results are more convincing than the therapeutic effects.

Ep 173-10:  A nice recent review by Baral on monoclonal antibodies under development.

PANSARBECO

Ep 173-11: Chee-Wah in NEJM (Sept 2021) reports on a very remarkable phenomenon: when SARS-COV-1 infected and survived subjects are vaccinated with the Pfizer vaccine, they make high tittered “pansarbeco cross-neutralizing antibodies”: they neutralize not only SARS-COV-1 and -2 (including the VOC), but also related bat- and pangolin viruses and they have a high number of cross-reacting B cells. (See Fig p. 4)

Comment:  The fact that the human B cells can mature to produce such broad cross-neutralizing antibodies has important prophylactic and therapeutic implications:

• A Pansarbeco vaccine, based on mRNA of SARS-COV-1 and SARS-CoV-2 may induce protective immunity against a wide range of Coronaviruses and their variants.  
• With modern technology, it should be easy to generate potent cross-neutralizing monoclonal antibodies for early treatment of Coronaviruses.

General conclusions:

• Both mRNA vaccines can now be considered safe and efficacious for adolescents.
• Existing monoclonal antibody treatment seems to act better as passive prophylaxis than as early treatment.
• There is hope for a Pansarbeco vaccine and more powerful and broad neutralizing antibodies.

Clearly positive messages!

Best wishes,

Guido