19 Nov 2021 Episode 189 Update on third dose, breakthrough, women and children

Fri, 11/19/2021 - 09:34

Dear colleagues,

This Episode follows up on the most recent information on vaccine efficacy, breakthrough infections and children, mostly based medRxiv preprints.

Vaccine Efficacy (VE) of third dose

Ep 189-1 A: Andrews showed in Sept that VE after two doses strongly decreased after 20 weeks in UK Summary of Tables 1-3: see Word attachment. 

(At first view, a bit strange that after 20 weeks protection against death is better than against hospitalization:  presumably not all residents of long care facilities were hospitalized before dying?)

Ep 189-1 B: Andrews now reports on VE after 3rd dose (with Pfizer) against symptomatic Delta disease starting 2 weeks after the jab in UK:

As compared to unvaccinated controls:

  • When first 2 doses with AZ: 93 %
  • When first 2 doses Pfizer: 94 %

As compared to people who received 2 doses only:

  • With AZ: 87.4 %
  • With Pfizer: 84.4 %

Clearly, this level of protection is back to the original Pfizer level (see figures in bold).  The difference is that after the original 3 doses the Alpha variant was predominant and now the more infectious Delta variant. 

Ten million dollar question: will the protection be more persistent after 3rd dose?   

Ep 189-2:  A single author from Dakha (Dr.  Ashraful Hoque) reports on the effect of a 3rd Pfizer dose in 20 “long-COVID” subjects, who experienced a breakthrough infection within 1-2 months after their 2 doses of Astra-Zeneca in March.   These subjects prexented rather non-specific symptoms (unusual fatigue, palpitation and insomnia).  After their 3rd dose, the anti-RBD antibodies rose, as expected, but the C-reactive protein levels also dropped significantly, as a potential evidence of reduced inflammatory activity.  There is, however, no mentioning of clinical improvement….


Breakthrough infections (BTI)


Ep 189-3: Kitchin et al in South-Africa confirm in a cohort of health care workers that the single dose Janssen Ad26-CoV2 S vaccine induces decent neut Ab titers (50 % inhibition at 1/100 dilution) against the D614G strain (only 1 mutation versus the Wuhan strain) and this neut remained stable over 6 months. Neutralization was much lower and often absent against the  beta-gamma-delta and other variants and no neut against SARS-CoV-1 was found (Fig 1 p. 10 and  p 11). 


The new observation is on 6 mildly symptomatic BTI, occurring 4-5 months after vaccination.  In these individuals, Neut Ab against all variants, including SARS-CoV-1, rose very significantly (Fig 1 and 2), suggestion, but not proving a broad protective immunity.


This observation reminds of the effect of a third dose in vaccinated, but non infected subjects and of a first vaccine dose in primarily infected subjects (see Ep 185-6 and -7).


Ep 189-4: A thorough analysis of 109 BTI in Florida

  • 75 % of BTI with Delta about 3 months after full vaccination;
  • Viral load in BTI on average 40 % lower than in unvaccinated with broad range and 50 % with a sufficiently high value for transmissibility.
  • BTI represent only 2 % of all cases, with no evidence of severe/fatal COVID: showing good protection by the vaccine, but asymptomatic BTI may have been missed.


→ Important to assess if additional boosters will reduce BTI occurrence and transmissibility

Will the virus be able to adapt to vaccine-induced immunity and increase transmissibility?


Ep 189-5: Pulliam reports a retrospective analysis of reinfections in South-Africa.  In this case reinfection is a new positive test at least 90 days after the first one, no molecular or clinical analysis.


The encouraging finding is that rates of reinfection during the second (beta) and third (delta) wave were rather LOWER than during the first (D614G) wave


Consistent with a scenario of variants with increased transmissibility but little or no immune evasion


Ep 189-6: Bozio MMWR Nov 2021: Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19–Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity between Jan  and  Sept 2021.


The adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection (95% confidence interval = 2.75–10.99).


This results differs from other studies that did not find such a big difference or no difference at all.

- One factor is the more time elapsed since the mRNA vaccination, the higher the chances on BTI.

- Another factor is whether also asymptomatic or mild (non-hospitalized) patients are taken into account.


Vaccination in pregnant women, children and youngsters


Ep 189-7: Ateyo maternal and placental Ab after vaccination in US.

  • Maternal vaccine-induced titers are comparable between mRNA-1273 (Moderna) and BNT162b2 (Pfizer) vaccination but lower after Ad26.COV2.S vaccination.
  • Efficient transfer of vaccine-induced antibodies to cord blood: antibody titer in cord samples with same order: mRNA-1273 =  BNT162b2 > Ad26.COV2.S.
  • Effect of timing (trimester) of vaccination:
    • First and third trimester vaccination resulted in enhanced maternal immune responses relative to second trimester.
    • Higher cord:maternal transfer ratios following first and second trimester vaccination reflect placental compensation for waning maternal titers.


Vaccination best early in pregnancy to maximize protection in mother and newborn.


Ep 189-8: Hongru Li on the need to vaccinate children under 12 in China, based on a Delta outbreak.


In this local surge in Putian, Fujian, the index was a middle-aged male, infected during quarantine after entry into China and transmitted the SARS-CoV- Delta to his two children (G1).

The activities of the children in the school spread the virus to their classmates (G2), which further extended the transmission to the factories(G4) through familiy contact(G3).

All of these cases were epidemiologically or genetically traced back to the first case.


The conclusion is nuanced:

The Chinese government has recently approved the emergency use of COVID-19 inactivated vaccine in the population aged 3-17. However, as the immune system of children, especially infants, is in the process of continuous development and improvement and the relevant application data of covid-19 vaccine is limited at present, more clinical trials should be conducted to clarify the efficacy and risk.

Accordingly, it is suggested that COVID-19 vaccination for children should be promoted in an orderly manner and that the effectiveness and adverse reactions of vaccination should be closely  monitored.


Ep189-9:  Lane on myocarditis and pericarditis after mRNA vaccine in Europe, UK and US:  in fact no surprise, but really big data base:


Younger vaccinees (< 30 yrs) more frequently report myocarditis and pericarditis

- male predominance

- more frequent after 2nd dose and after Pfizer

The clinical course of these events is typically mild, with full recovery in most cases.


Unfortunately the exact frequency is not shown.  Two deaths were reported in UK, but in one case it was an older subject. 


Other papers of interest


Ep 189-10: Tauzin from Canada shows that spacing the two Pfizer doses to a 16 weeks instead of a 4 weeks interval in naïve individuals results in better humoral immune responses, including neutralization titers and breath that resemble those in infected + vaccinated subjects

This strategy could be advantageous, but needs to be weighed against the risk of getting infected between the 2 doses when protection is suboptimal.


Episode 189-11: Xiang-Jiao Yang shows that different delta subvariants have spread in Israel, Qatar and Bahrain, which may partly explain the different epidemiological characteristics.  The author recognizes however, that other factors, such as timing in relation to “infection wave”, final coverage of vaccination, as well as behavioral factors may play a role.  The author also claims (but does not really show) that the additional jab could control the epidemic in the three countries, suggesting that the various delta sublineages remain sensitive to booster vaccination


Ep 189-12: Tallmadge compares sensitivity of various paired respiratory samples in five assays.


Of the 63 sets, SARS-CoV-2 was detected in from 62 Nasopharyngeal (NP) specimens, 52 bilateral anterior nares (AN) , 59 saliva, and only 31 sublingual (SL) specimens by at least one platform.


Of 50 sets, infectious SARS CoV-2 was isolated from 21 NP, 13 AN, 12 saliva, and one SL specimen.  


Conclusion: The less sensitive saliva and AN specimens are acceptable alternatives for NP

  •  symptomatic SARS-CoV-2 diagnostic testing
  •  surveillance with increased sampling frequency of asymptomatic individuals.


Ep 189-13: An update and overview of Spike protein-based vaccines in development.  Published results from Novavax (US) and announced results from Clover (China) look promising (see Episode 179-14and 15). There are several more developers in India, Canada, UK and South-Korea (Table p. 4).  The development has been slow and upscaling is more cumbersome than with mRNA and Adenovectors, but the big advantage is that protein-based vaccines could overcome vaccine hesitancy, in view of the widely available and accepted hepatitis B and Papilloma vaccines….


Best wishes,