Sun, 07/04/2021 - 20:53
While working on Episode 150 (Mucosal immunity and intranasal vaccines, I wanted first to share two opinion papers, the first (Ep 151-1) published in “De Morgen” (with Hans Snoeck and Linos Vandekerckhove), the second (Ep 151-2 A) is part of an ongoing discussion on how to overcome the huge gap between vaccination in North and South and the often heard remark that we should refrain to vaccinate our children and share our vaccines with the South (Ep 151-2 B), which I think is a false dilemma.
Sorry for those who have received/read these contributions already.
I do realize, however, that the value/place of inactivated vaccines remains a matter of debate, mainly because formally published data on efficacy in phase 3 and real world follow-up remain scarce.
Starting with what we already knew:
Ep 151-3: Formal paper in JAMA on the two inactivated vaccines from China National Biotec Group (better known as Sinopharm) in Bahrain and the Emirates: efficacy against symptomatic COVID-19 at least 14 days after 2nd dose: 72.8% for the WIV04 and 78.1% for the HB02. Remarks:
- Mainly young adults: only 1.5 % older than 60
- Only 2 severe cases, both in the Alum placebo group.
Ep 151-4: Preprint by Palacios in Brazil on Coronavac from the Chinese Sinovac Co.: it showed 50.7 % efficacy against symptomatic COVID. All 6 severe cases were in the control arm. Notes:
- This study was 3 X smaller, included mainly HCW, also 5 % over 60 and 55 % subjects with underlying disease:
- Efficacy was the same (51 %) for individuals below and above 60 years. It was lower (39 %) for those with cardiovascular disease, similar (49 %) for those with diabetes and higher (75 %) for obese subjects!
- Titers of neutralizing antibodies against the Brazilian variants (B.1.1.28, P1 and P2) were comparable, but fewer subjects in the older age group actually seroconverted!
Unfortunately there is as yet NO published phase 3 data on the Indian inactivated Covaxin by Bharat. In fact, it seems that the trial has been interrupted already in January and roll out has started in view of the emergency situation in India. See
https://qz.com/india/1951939/how-india-approved-bharat-biotechs-covaxin-vs-covishield/
Ep 151-5: provides a nice meta-analysis of known data with ready-to-use figures: clearly the efficacy of the inactivated vaccines is lower than the Adeno’s and much lower than mRNA, but their side effects seem very acceptable
Ep 151-6 A and B: two contributions by Smriti Mallapaty (a senior science journalist) in Nature on the approval of the inactivated vaccines by WHO
- Unpublished efficacy results on Coronavac: 67 % in Chile and 83 % in Turkey, clearly higher than the 50.7 % in Brazil
- Many remaining questions:
- Protection of elderly, children, pregnant women and immune deficient patients?
- What type of immune responses (only antibodies or also T cells), how long protection lasts?
- How effective against variants?
The following papers partly address some of those concerns
151-7 A: Clear beneficial effect of mass vaccination on elderly mortality in Brazil:
- Vaccination coverage (first dose) of 90% was reached by week 9 for individuals aged 80+ years and by week 13 for those aged 70-79 years.
- Coronavac was mainly used in 80+ and Astra-Zeneca more in 70-79 years old.
- COVID-19 deaths at ages 80+ years was over 25% in weeks 1-6 and declined rapidly to 12.4% in week 19, whereas proportionate COVID-19 mortality for individuals aged 70-79 years started to decline by week 15
151-7 B: Mass vaccination with Coronavac in the town of Serrana (population 27,000):
Following high coverage with Coronavac in early 2021, reductions of 80 % in symptomatic cases, 86% in hospital admissions and 95% in deaths were observed by the end of May.
Ep 151-8: Sapkal compares the neutralizing antibodies from convalescent and the Indian Covaxin (Bharat) vaccinated people against the gamma variant. While convalescent sera have a similar neut activity against the D614G and gamma, the vaccinated sera are significantly less active, but the difference is limited.
Ep 151-9: A phase ½ study of Coronavac in children and adolescents (3-17 yrs), showing good immune responses, including neutralizing antibodies with 2 X 3 µg dosis. However, difficult to know how these titers compare with other vaccines. Also no comparison made with sera from convalescent patients (which is usually done for other vaccines).
Ep 151-10: Antibody responses to Coronavac in HCW and elderly with immune deficiency:
- Among hospital workers, the vast majority of patients with IMD and immunocompetent controls developed a significant humoral response following the administration of the second dose of inactivated COVID-19 vaccine.
- This was also true for the elderly population, albeit with lower antibody titers.
- Immunosuppressive use, particularly rituximab significantly reduced antibody titers.
- Antibody titers were significantly lower among those aged ≥ 60 years both in immune deficient patient and control populations.
Clearly, at first view not so different as with other vaccines, but no direct comparison made with other vaccines or convalescent sera and no data on efficacy.
Ep 151-11: Immune responses to an unspecified inactivated vaccine from Yunan university after 6 months waned, but a boost re-induced strong neutralizing antibody as well as IFN-g producing T cells. The figure with the data is not readable and the vaccine was not standardized (first inactivated with formaldehyde , later with beta-propiolactone). The question remains whether waning immune responses are seen with the standardized inactivated vaccines (Coronavac, Sinopharm…) and whether there is a need for a third dose indeed….
What about side effects?
- General
Ep 151-12: Both Covishield (Indian versus of Astra-Zeneca) and Covaxin (Indian inactivated BBV152) were found to be safe in auto-immune and non-auto-immune rheumatoid arthritis. Purely observational. Small number of subjects receiving the inactivated vaccine.
- Neurological
Background:
- COVID-19 itself can present with a variety of neuroimmune complications, including Guillain-Barré syndrome, neuromyelitis optica spectrum disorders (NMOSD), Miller Fisher syndrome, polyneuritis cranialis, myasthenia gravis, and myelitis.
Ep 151-13 A: Case report on neuromyelitis optica spectrum disorder after inactivated
virus vaccination for COVID‑19 (not clear which one).
Ep 151-13 B: Bell’s palsy, stroke, Guillain-Barré etc have been reported after vaccination with other COVID vaccines in US, but a causal relationship was not established.
- Other auto-immune disorders
Ep 151-13 C: Three cases of subacute thyroiditis following Coronavac in Turkey, 4-7 days after vaccination in 3 women, of whom 2 were breastfeeding.
- Interpreted as ASIA (auto-immune-inflammatory syndrome induced by adjuvants).
- Also occurs in the context of COVID-disease.
- Treated with corticosteroids
Ep 151-13 D: Once case of life-threatening haemophagocytic lymphohistiocytosis (HLH) after inactivated vaccine in China (not specified which one):
- No genetic predisposition, but EBV as potential co-factor.
- HLH is related to the MIS-C syndrome that occurs in children, adolescents, but sometimes also in young adults during COVID
- Herpes zoster reactivation
Ep 151-13 E: Case report from India after Covaxin in a 60-years old man and reference to similar cases after inactivated COVID and Influenza vaccines in Turkey and US.
Are inactivated vaccines inferior?
Ep 151-14: Two authors from Oman observed remarkable differences in the evolution of the SARS-CoV-2 deaths per million in neighboring Bahrain and Qatar. By June, both countries had provided at least one dose of a COVID vaccine to > 50 % of the population, but deaths dropped in Qatar (solely relying on mRNA vaccines) and increased in Bahrain (mainly relying on inactivated Sinopharm). See fig 1 p. 10)
They further analyzed 10 countries with similar vaccination coverage of which
- 5 mainly relied on inactivated vaccines: Bahrain, Chile, Hungary, Maldives, and Mongolia.
- 5 relied on mRNA and/or Adeno: Israel, Malta, Qatar, UK and US
From Fig 2 p. 11, it is very evident that the latter 5 were better off in terms of COVID deaths per million early June.
Nevertheless, revisiting the same website now (early July) only in Mongolia (which had almost no cases in 2020) the epidemic is on the rise, while in most other countries (except Chile; it shows a decreasing trend over the last month….. And, of course, there are a lot of “confounders”….
Ep 154-15: Nice study, based on published trial to show the correlation between efficacy to prevent symptomatic COVID and ELISA or neut titers (after calibration to titers of human convalescent sera). The inactivated Coronavac in the Brazilian trial (Ep 151-4) is clearly the weakest. However, as discussed in Ep 151-6 other, non-published results of Coronavac seemed better and also the Sinopharm vaccines scored better (Ep 151-3).
And what happens in Europe in this field?
There is one inactivated candidate by the French company Valneva in development, but it is very hard to find data. In fact, it seems that a comparative (non-inferiority?) phase 3 trial with Astra-Zeneca is still recruiting. See two press communications below
Preliminary conclusions
- There remains a discrepancy between the paucity of well-controlled and peer-reviewed data on inactivated vaccines and their widespread use all over the world
- It seems that the Coronavac and Sinopharm vaccines are active against symptomatic COVID and there is evidence of their usefulness in Brazil, but many questions remain. It is really strange that so few good clinical studies have been published, because very nice preclinical and early clinical (phase ½) data on the Chinese vaccines were already published more than one year in top journals like Nature and Cell.
- It is also difficult to understand why the big European and American vaccine producers (Mérieux, GSK, Merck…) have not even tried to develop an inactivated vaccine, even not as plan B.
I’m eagerly awaiting more solid publications. In the meantime, I really think that we should give the inactivated vaccine “the advantage of the doubt” for the reasons that I explained in my “opinion” (Ep 151-2 A).
I’m also curious to know if some of you has information that I could not find.
Best wishes
Guido
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