1 nov 2021 Episode 185: Heterologous prime boost, third dose and young children.

Dear colleagues,

After a short interruption, I found so much new interesting information that it is rather easy to pick the “low hanging fruits”.   Here we go.

Evidence in favor of heterologous prime boost: Adeno + RNA

Ep 185-1: Callaway summarizes the evidence for Nature News.  Most of it is “circumstantial”, but there are two really convincing papers:

Ep 185-2: Pozetto in Nature presents an observational study in over 13,000 HCW in the Lyon area, comparing Astra-Zeneca + Pfizer (heterologous) with twice Pfizer (homologous).

• Fig 1 shows that those who received Astra-Zeneca as prime and Pfizer as boost had an almost 50 % reduced chance on PCR + infection, as compared with Pfizer prime + boost.
• Fig 2 indicates that the neutralization of the heterologous regimen is more pronounced against Alpha, Beta, Gamma and Delta variants
• Fig 3 provides some explanation for the beneficial effects of heterologous regimen: more IgG class switched and activated memory B cells after the heterologous boost  and more IFN-gamma producing CD4 T cells after the Astra-Zeneca prime.

Clearly, it looks as if the enhanced early CD4 T cell response after Astra-Zeneca sets the scene for better “maturation” and increased breath of the B cell responses.

Ep 185-3: Nordstrom in medRxiv presents a cohort study in the Swedish general population, comparing two heterologous regimens (Astra-Zeneca + either Pfizer or Moderna) with each of the homologous regimen: over 700,000 people in total.  The outcome is symptomatic infection

Conclusion

• According to Pozetto Astra-Zeneca + Pfizer protects better against infection than homologous Pfizer.
• According to Nordsstrom the heterologous schemes are more protective against symptomatic infection than the Astra-Zeneca homologous scheme, but still inferior to both mRNA homologous schemes.

Efficacy of third dose:

1. Healthy subjects (and general population)

Ep 185-4: A press release from Pfizer, announcing favorable results of a randomized phase 3 trial of a third dose in adults: “ A relative vaccine efficacy of 95.6% against disease during a period when Delta was the prevalent strain”

Ep 185-5: A “real world” observational study in Israel (Bar-On medRxiv) on third Pfizer dose: over 10 fold decrease in infection and disease as compared to two doses only.

Ep 185-6: Iketani meRxiv application of an heterologous  third dose (Janssen Ad26COV-2 S) after two doses of Pfizer boosts Ab response and broadens it to variants of concern (alpha, beta, gamma, delta).  

Ep 185-7: Maria Elena Romero (medRxiv): 3rd Pfizer dose 6 months after 2 doses in HCW:  strong booster effect.

Ep 185-8:  Wang medRiv A third booster dose of inactivated vaccine CoronaVac produces a high humoral immune

response via a sustained evolution of antibodies capable of effectively neutralizing SARS-CoV-2 variants of concern.

Ep 185-9:  Lei Yue: similar message in Em Micr infect

2. Immunosuppressed patients

Ep 185-10: Betrand in Kidney International on kidney transpla,nt patients under immune suppressive therapy:

• after a  second dose of Pfizer 37 % seroconverted;  
• after a third dose 61 %  had Spike-specific antibodies.

Ep 185-11:   Similar finding by Karaba (medRxiv), who used 70 % Pfizer and 30 % Jansssen vaccines report very similar findings on neutralizing antibodies.   The third vaccine induced a very clear rise of neutralizing antibodies against all variants (see Fig2 p. 26)  Neutralizing titres were, however, much lower than in healthy controls and 32 % of organ transplant patients remained negative. 

Ep 185-12: Shroff (Nat Med) provided a third Pfizer dose to 20 patients with solid tumors on immune suppressive chemotherapy.  Sixteen of those demonstrated a median three fold increase in neutralizing antibody titers.

Conclusion:

There is a clear-cut immunological benefit of a third dose in terms of increased Spike antibody levels, neutralizing capacity and breath against variants in healthy persons, regardless whether mRNA, adenovirus or inactivated vaccines were used.  

A similar, but less pronounced effect is seen in immune suppressed subjects (organ transplant and cancer), where increased seroconversion is observed. 

The population study from Israel also suggests a clear-cut protective effect.    

CHILDREN

Ep 185-13: In round 14 of the UK REACT-1 study (REal-time Assessment of Community Transmission-1, two observations are striking for September:

1. School children (5-17 yrs) are the most infected
2. Vaccine efficacy against infection is waning: now at 45 % for Astra-Zeneca and 71 % for Pfizer.

Ep 185-14: FDA formally advises Pfizer vaccination for 5-12 years old children, after a careful weighing of risks and benefits in various scenarios of the epidemic.  More information can also be found at the website of CDC

https://www.cdc.gov/vaccines/covid-19/planning/children.html#covid19-vax-recommendations

Best wishes,

Guido