21 July 2021 Episode 155 Indian vaccine, breakthrough infections, delta variant and genetic diversity

Dear colleagues,

As could be expected, more information on breakthrough infections after vaccination is emerging. But, I will start with the long awaited results of the phase 3 trial of COVAXIN (also referred to as BBV152), the Indian inactivated vaccine.

Indian vaccine and second wave

Ep 155-1: As compared to the Chinese inactivated vaccines, COVAXIN is also inactivated with beta-propiolactone and formulated as a 6 µg dose, but, in addition to alum, a Toll-like receptor 7/8 agonist is present to enhance Th1 responses (Algel-IMDG). 

• The trial was done between 16 Nov 2020 and 6 January 2021, hence before the advent of the huge Indian wave, but nevertheless quite some cases of the “Indian” kappa (B.1.617.1) and delta (B.1.617.2) were noted (see below).
• At screening 30 % of subjects were found actually infected (PCR+) or previously infected (seropositive).  They remained included for safety, but excluded for efficacy. Effective size of trial for safety 25,798; for efficacy 16,973
• About 10 % of participants were > 60 and  about 20 % with co-morbidities.
• At first view much less local and systemic side effects than with mRNA and Adenovirus vaccines
• Efficacy:
  • Symptomatic COVID:
    • Overall 77.8 % (130 cases in total)
    • In > 60 yrs old: 67.8 % (21 cases)
    • With pre-existing condition: 66 % (49 cases)
  • Severe COVID:  93 %   (16 cases)
  • Asymptomatic infection: 63 % (47 cases amongst 6289, who consented with PCR every month).
• Amongst the 177 breakthrough PCR(+) 79 variants were noted.
  • For all variants, efficacy remained high (70 %), but it was lower for delta (65 %) than for kappa (90 %).
  • Infections in vaccinated had clearly a lower viral load than in non-vaccinated. 

Conclusion: This inactivated vaccine (COVAXIN) seems to have a similar efficacy as the Adenovirus vaccines, but clearly lower than the mRNA vaccines and to have less side effects than both.  The efficacy is lower at higher age, with co-morbidities and against infections with the delta variant.

 Ep 155-2: An epidemiological description of the catastrophic second wave in India.

• In January 2021 21.6 % of the adult population had (serological) evidence of SARS-CoV-2 infection, implying a serious underreporting of cases (only 6 % of real infections reported)
• The effective reproductive number  rose over 1 on Feb 14.
• By April 1st only 2 % of the population was fully vaccinated (5.2 %  had 1 shot) of either COVAXIN or Covishield (Indian Astra-Zeneca).
• Table 1 p. 35 shows a detailed comparison of characteristics between first en second wave.

Breakthrough infections (BTI)

1. Some early US and UK BTI data with Pfizer

Ep 155-3: An early CDC report mentions 10,262 BTI between Jan1 and April 30, of which 10 % was hospitalized and 2 % died.  VOC were already prevalent at 60 % alpha > epsilon (B1.427/1.429) > gamma > beta.  At that time, mostly mRNA vaccines were used and the overall BTI ratio is < 1%, but this is a passive detection. 

Ep 155-4 a: A very large prospective study > 20,000 HCW in England, showing an efficacy of 70 % after 1 dose of Pfizer mRNA and 85 % after two doses in the first months of 2021 when the alpha variant was prevalent.

Ep 155-4 b: :  Data from Public Health England  of > 12,500 sequenced cases

• Efficacy of vaccines against symptomatic disease 2 weeks after full vaccination:
  • Pfizer-BioNTech vaccine was 88% effective against delta B.1.617.2, compared to 93% against the alpha B.1.1.7
  • AstraZeneca vaccine wase 60% effective against delta and  66% against alpha
• Efficacy 3 weeks after 1 dose
  • Both vaccines were 33% effective against delta and around 50% against alpha.

2. Recent Indian BTI data mainly with Covishield during delta wave

Ep 155-5:   Small study in 123 HCW in New Dehli, vaccinated with either 28 Covaxin (inactivated) or 85  Covishield (Astra-Zeneca), just before the second wave: mild BTI in 13 % (only 1 hospitalized). Not clear if difference between Covaxin and Covishield.

Ep 155-6: Larger study in 1639 Indian HCW vaccinated with Covishield versus 219 non-vaccinated Jan-May 2021:  BTI in 21.5 % of unvaccinated > 13.6 % in partly vacc > 8.6 % in fully vaccinated.

• Implying 60 % vaccine efficacy (corresponds to trial results of Astra-Zeneca)
• No difference in viral load between groups.
• Three severe cases and 1 death in unvaccinated, none in vaccinated.
• Reinfection in 4 vaccinated HCW: all mild disease.
• All but one either delta (B.1.617.2) or kappa (B.1.617.1)

Ep 155-7: Another study on 461 fully Covishield vaccinated Indian HCW: 86 (18.6 %) got infected with 10 hospitalizations, of whom 2 ended in ICU and 1 of those died.  A clearly less favorable outcome than the previous study.   

3. Some recent BTI data from US

Ep 155-8: BTI after mRNA vaccination in > 23,000 HCW in New-Jersey between Jan and end of April:

• Only 0.6 % BTI overall of which only 0.15 % in fully vaccinated subjects.
• Only 5 hospitalizations in partly vaccinated.
• No difference of N501Y or E484K/Q between vaccinated and unvaccinated

Ep 155-9: BTI after either mRNA (100,00 Pfizer; 20,000 Moderna) or Adeno Janssen (2,800) in > 125,000 vaccinated general population in NYC 1st Feb till end of April:      

• Only 0.07 % BTI in fully vaccinated (86 subjects = 1.2 % of all SARS-CoV-2 cases in that period)
• No difference according to vaccine administered.
• Seven required hospitalization and 1 elderly with multiple co-morbidities died.
• Same distribution of alpha and Iota (B1.527) variants and similar viral loads in vaccinated and unvaccinated cases.
• Nevertheless an enrichment of NTD deletions and RBD escape mutations in BTI compared to unvaccinated control sequences.

Ep 155-10: Interesting (and frightening) case report of two Indian travelers in their late sixties, vaccinated with Covaxin 10 days before, who tested negative in PCR before travel and attended an open air wedding in Houston.

• Both developed symptoms soon after and one of them (without co-morbidities) died.
• They infected 4 other guests in their fifties and sixties, who were fully vaccinated, all symptomatic and 1 severe.  (see Table 1 p. 12)
• All infected with Delta variant.

In vitro neutralization against VOC

Ep 155-11: Study from Chile, where vaccination has relied mainly on the inactivated Chinese CoronaVac and much less on Pfizer.  

• As you know, Chile has a high rate (> 60%)  of full vaccination, while infections continued to rise until recently (but coming down since last month).
• The dominant VOC are gamma (Brazilian P1) and lambda (C37)  (See appendix p.14).

This study shows that, as compared to WT virus)  CoronaVac plasma is 2.3 less effective against alpha, 2.33 less against gamma and 3.05 against lambda (p. 12).  The authors further state that lambda is also more infectious and that it shares a critical L452Q mutation with delta.

The suggestion is that CoronaVac does not protect enough against the dominant gamma and lambda variant. However,

• the authors did not make a comparison between CoronaVac and Pfizer plasma
• there is no epidemiological data on BTI.

Ep 155-12:  A very nice study, comparing plasma from convalescent, mRNA or Ad26 vaccinated subjects against the most important VOC (alpha, beta, delta and lambda).

• Please have a look at p. 28 for the genetic differences: delta plus has an additional K417N
• On p.26 panel B it is evident that
  • mRNA vaccines induce higher neut than either convalescence or Ad26
  • Susceptibility of alpha is similar as D614G, but all other VOC are much less sensitive
  • Pfizer and Moderna are equivalent, but Ad26 induces very poor neut against beta, delta or lambda

Epidemiological and genetic evolution related to vaccination

Ep 155-13: Modeling future epidemic in US:

• Best case (only wild-type virus): 61 % vaccination is enough for herd immunity.
• Intermediate scenario: new variant can cause a significant disease if
  • (i) the vaccine coverage against the wild strain is low (roughly < 50%),
  • (ii) the variant is much more transmissible (e.g., twice more transmissible) or
  • (iii) the level of cross-protection by vaccine is relatively low (e.g., less than 70%).
• Worst case =  no cross-protective vaccine efficacy against a variant that is 2 X more infectious → 55 % of the U.S. population will be infected by March  2023 and 2.2 million deaths.

Ep 155-14: COVID-19 vaccines dampen genomic diversity of SARS-CoV-2

• The diversity of SARS-CoV-2 genomes is decreasing since mass vaccination has started (Fig 1 p. 11).
• Vaccinated patients generally had lower rates of comorbidities and complications compared to the overall study population, while the unvaccinated patients generally had higher rates of both comorbidities and complications.
• B-cell epitopes exhibit more mutational diversity in unvaccinated than in vaccinated subjects. (Fig 4 b p. 14)
• T cell epitopes are significantly less mutated than B cell epitopes → vaccines that predominantly rely on T cell immunity a more durable protection against VOC?  (Fig 2 p.12)

Conclusions:

1. The Indian inactivated Covaxin seems to have an efficacy that is comparable with the Adenovirus vaccines, but has less side effects.  
2. General population data from England show that full Pfizer vaccination is 93 % effective against alpha and 88 % against delta; whereas Astra-Zeneca is 66 % against alpha and 60 % against delta.
3. Full Covishield (= Astra-Zeneca) in Indian HCW resulted in 8.6 – 18.6 % breakthrough infections
4. Data from NYC and New Jersey show very few BTI after mainly mRNA vaccination, before the advent of delta.
5. Frightening case report on delta BTI infection after Covaxin vaccination in Indian couple and transmission to 4 fully mRNA vaccinated people during open-air wedding, with serious complications and even 1 death.   
6. As compared to convalescent patients, mRNA vaccinees induce higher, but Ad26 vaccinees lower (in vitro) neutralizing Ab to beta, delta and lambda VOC.  Similarly, the Chines inactivated Coronavac also induces weak neut against lambda.
7. In general vaccination seems to
   • Decrease global genetic diversity.
   • Is associated with lower comorbidities and complications in case of BTI

Much lower rate of T cell epitope mutations suggest role for T cell immunity in vaccination strategies that will be less susceptible to VOC.   

Best wishes,

Guido