25 July 2021 Episode 156: India’s DNA vaccine, more on delta, more on ChAdOx-1 and more on children.

The Indian DNA vaccine

Ep 156-1: Zydus-Cadila company has submitted a file to the Indian regulator based on a favorable phase 3 study (unpublished).

• The vaccine ZyCoV-D = plasmid DNA encoding whole spike region of Wuhan Hu-1 strain
  • 3 times 3 mg intradermally via needle free applicator
  • No formulation and no viral vector involved, hence no immune reactions expected.   
  • Can be prepared in normal lab (BSL-1)
  • Can be stored in regular fridge
• According to this press release: phase 3 on 28,000 people, including 1,000 12-18 yrs
  • 66.6 % efficacy against symptomatic PCR(+) COVID after 3 doses
  • 100 % effective against “moderate” disease and no deaths, even after 2 doses
  • Safe in children.

Ep 156-2: Early mice and rabbit data, showing induction of neutralizing antibodies, Th1 T cell responses and remarkably broad biodistribution of the DNA in tissues (!)

Ep 156-3: Preprint about immunization and protection of macaques in small groups of 4, comparing needle-based and needle-free injections.  The authors claim that 3 X 2 mg needle-free injections are very efficacious in terms of induction of neutralizing antibodies and protection against infection.  Honestly, I feel those claims are not clear from the data.   

Ep 156-4: Results of a small phase ½ trial in EBioMed:

• Acceptable safety (25 %, mainly local side effects), mostly after first dose.  Hence no “sensitization”.
• The 3 X  1 mg dose (either needle or needle-free) was clearly too low (only 1/3 seroconverted), while in the 3 X 2 mg 10/10 converted after needle and 8/10 after needle-free injections.
• With regard to neutralizing Abs (see Fig 4 p. 7):
  • The median neut titers after 3 X 2 mg at day 84 seem comparable with those from convalescent plasma donors
  • Very strange that several subjects in the 1 mg groups showed already neutralizing titers before vaccination, although previous SARS-CoV-2 infection was excluded.
  • Also Table 4 and 5 show some strange results: in the 2 mg needle group only 5/10 subjects showed an increase of neutralizing titers.  

Conclusion:

• The press release about the phase 3 trial (using 3 X 3 mg dose) suggests that this DNA vaccine has about the same efficacy as the Adenoviral vaccines and may even be better in terms of averted hospitalizations and deaths and the safety profile seems also very favorable.
• The preclinical data in macaques as well as the phase 1 and 2 study, both using 3 X 2 mg, however, suggest a rather weak immunogenicity.  
• Apparently, the company shifted from 3 X 2 mg in phase ½ to 3 X 3 mg in phase 3. Is that enough to explain the favorable results?

More on delta

Ep 156-5 a: Comment in Nature, referring to the next preprint: the very fast spread of delta can be explained by a shorter incubation time (3.7 days instead of 6) and a much higher viral load.  Whether delta also causes more disease and how good it is at evading immunity is not yet clear.

Ep 165-5 b:  Interesting additional elements in detailed transmission in Guangzhou:

• The shorter incubation time of delta implies that a negative PCR is only valid for 2 days, if you want to prevent any chance of transmission.
• The transmission bottleneck (how many viruses “survive” transmission and cause new infection) is calculated at 1-3 virions, implying that most minor variants will not make it.
• Nevertheless, minor variants were documented in 4 out of 30 transmissions.

Ep 165-5 c: Delta variant and breakthrough infections (BTI) in Houston:

• Delta had higher initial viral load, but not associated with higher hospitalization or death. 
• Delta more frequent cause of BTI (full vaccination): 19.7 % versus 5.8 % for other variants.
• Overall, BTI as compared to unvaccinated infections had lower initial viral load and patients were less likely to be admitted to hospital.

Real world efficacy of ChAdOx-1 (Covishield-Astra-Zeneca) and CoronaVac: test-negative case control studies in India and Brazil

Ep 165-6: Covishield 360 HCW in Pudicherry (March-May), while delta variant was more than 70 %

• Vaccine efficacy against symptomatic SARS-CoV-2 after 1 dose 58 %, 2 doses: 64 %.
• VE against severe disease: 95 %, but few cases (wide CI 44-100).

Ep 156-7a: Astra-Zeneca in Soa-Paolo on > 61,000 subjects > 60 years, who experienced acute respiratory illness between Jan and July 2021, when gamma variant was dominant.

• VE 28 d after 1st dose: 33 % against COVID, 55 % hospitalization and 66 % against death. 
• VE 14 d after 2nd dose: 78 % against COVID, 88 % hospitalization, 94 % against death
• Single-dose VE against hospitalization and death was lower among older individuals, but these analyses lacked sufficient power

Ep 156-7b: The same authors also evaluated CoronaVac (the Sinovac inactivated vaccine) in a similar setting in  Sao Paolo: > 43,000 adults, but now > 70 yrs

• VE 0-13 days after 2nd  dose only 18% against symptomatic COVID
• VE > 14 days after 2nd dose: 42 % symptomatic COVID; 49 % hospitalization and 71 % death
• Clear decline in VE after 2nd dose with age: 70-74 yrs: 62% against COVID; 80 % hospitalization, 86 % death.  See Fig 3 p. 26
• Note: the mean age in this study was 77, while it was 67 in A-Z study.

Ep 156-7c: A very confusing paper was published about a similar study with CoronaVac in HCW in Manaus, where they found:

• Increased chances of symptomatic infection 0-13 days after 1st dose (Odd’s ratio > 2) !!
• VE > 14 days after 1st dose = 49 %
• VE after 2nd dose: 36 %

Children and SARS-CoV-2 in England and US

Ep 156-8: Interesting study in English primary school, comparing seroprevalence in June and Dec 2020.

• In June 11.5 % resp 15.5 % of students and staff were seropositive (hence had been infected).
  • Live virus neutralization in 85 % of children with RBD (receptor binding domain) Ab.
  • Staff had quantitatively lower levels of Ab
• Six months later, about 80 % of children and staff kept their Ab.

Concluding: Our findings provide further evidence of a robust and sustained immune response in children following primary SARS-CoV-2 infection. Further studies are needed to assess protection against emerging variants of concern.

Ep 156-9: Overview of the SARS-CoV-2 in US children by the American Academy of Pediatrics.

• Over 4 million children have tested positive = 14 % of total US cases (29 million)

5.3 % of all US children (75 million)

• Weekly overview on p. 9 Fig 6: highest = 211,000 end Jan; lowest 8,500 end June, but now rising again to 23,000 mid-July.
• Almost 17,000 children have been hospitalized ( about 2.5 % of total hospitalizations)
• 346 children have died = 0.01 % of total infected children.

Ep 156-10 (a and b):  I could not find a scientific paper on the clinical impact of delta variant in children.  It is clear that the cases are rising again since early July, but the clinical picture seems not different from previous variants.  The two papers from regular press quote several experts, including Tony Fauci.  Their emphasis is on prevention of infection by vaccination and non-pharmacological interventions.

Remarkably, this week the Washington Post gives a lot of attention to prominent Republican (GOP) politicians, including senator Mitch McConnel, urging people to get vaccinated.  The GOP governor of Alabama, confronted with the highest hospitalization rate in months, stated that non-vaccinated people are “choosing a horrible life style of self-inflicted pain”.

Ep 156-11: Ongoing discussion whether or not it is a priority to get adolescents (12-18) vaccinated.  The UK takes a “conservative approach”: only vulnerable adolescents or those who live with vulnerable adults.  Other countries, like US, Israel and Malta are very actively promote mRNA vaccination in this age group, because

• herd immunity will not be reached by vaccinating adults only,
• some children do get ill and
• there is a possibility of deleterious effects of co-infection with other viruses (e.g. RSV).  

Ep 156-12: A very interesting analysis of myocarditis, the most common side effect by RNA vaccines in children.  A total of 323 cases have been confirmed in US. All recovered.

The summary is in Table 2 p. 4. Clearly, the highest risk is in young boys 12-17. However also in this group the balance of avoided hospitalizations and deaths remains clearly positive.

Ep 156-13:  The advice from the American Academy of Pediatrics (AAP) for school reopening is very clear and well-motivated:

Purpose: keeping students safe and physically present in schools.

• Vaccinate all eligible students and staff: at present from 12 years on, but trials with younger children are underway.
• Universal face masking from 2 years on.  
• Other non-pharmacological interventions (NPI) measures include  ventilation, testing, quarantining, and cleaning and disinfecting

Some overall conclusions:

1. Status of Indian DNA vaccine unclear: press release of phase 3 was very promising, but published preclinical and phase1/2 data not convincing.  DNA vaccines have been tried in humans since many decades without a true breakthrough.

2. Delta variant : higher infectiousness (including as breakthrough) presumably due to shorter incubation and higher respiratory viral load, but until now no evidence of higher intrinsic pathogenicity in adults or children.  Immune escape in vaccinated subjects possible.

3. Real world data on ChAdOx1 and CoronaVac:

• ChAdOx-1: favorable results in Indian HCW (during delta epidemic) and Brazilian elderly (during gamma epidemic).
• CoronaVac: clearly weaker protective effects in both Brazilian HCW and elderly (during gamma epidemic).

4. Children: while UK is taking a “conservative” approach, US and other countries favor maximum vaccination coverage as a strategy to re-open schools safely.  Myocarditis is not a reason to doubt about Pfizer vaccine in youngsters.  AAP also insists on NPI, including face masks from 2 years on.

Best wishes,

Guido