CME INDIA Presentation by Dr N K Singh.

Crucial to success of any COVID Vaccine: Trust it, have Confidence in it.

2020 has been a year you will want to delete for ever. But you will never be able to, even after getting 58 vaccines – against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – which are knocking the door. We discuss here only those which matter at present…But no need to be excited about encouraging findings. At present, 3 safe and efficacious COVID-19 vaccines exist, and a further 55 are in clinical trials. COVID-19 treatment and prevention is a gamble, without concrete evidence so far. We have some reason to suspect what might help or what not?

Just a reminder

The most important symptoms of COVID-19 are recent onset of any of the following:

• A new continuous cough
• A high temperature
• A loss of, or change in your normal sense of taste or smell. If you have the above symptoms, stay at home and arrange to have a test.

No Day Dreaming

• The vaccine cannot give COVID-19 infection
• Two doses will reduce only chance of becoming seriously ill.
• Science does not yet know whether it will stop people from catching and passing on the virus.
• So, it is important to follow the guidance in our local area to protect those around us.

Phase 3 data of Pfizer vaccine as on 08/12/2020

(Source-Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document)

• Efficacy: Benefit starts 14 days after the 1st dose.
• The known benefits among recipients of the proposed vaccine relative to placebo are:
  1. Reduction in the risk of confirmed COVID-19 occurring at least 7 days after Dose 2.
  2. Reduction in the risk of confirmed COVID-19 after Dose 1 and before Dose 2.
  3. Reduction in the risk of confirmed severe COVID-19 any time after Dose 1. The protocol-specified 2-dose vaccination regimen was highly effective in preventing PCR confirmed COVID-19 occurring at least 7 days after completion of the vaccination regimen.
• It takes about 2 weeks for the immune system to make sufficient antibody protection after vaccination.

Efficacy Table:

Adverse Effects:

• The chance of getting a severe adverse event – Low (0.5%).
• A severe event is more likely in the second dose than the first.
• It was less frequent among older adults compared to younger participants.
• Unexpected adverse event in the vaccine group – Swollen lymph nodes (lymphadenopathy) – bell’s palsy.
• 6 people died during the trial. Deaths were NOT related to the vaccine. Mostly related to heart attacks.
• Safety data comes from from approximately 38,000 participants ≥16 years of age randomized 1:1 to vaccine or placebo with a median of 2 months of follow up after the second dose. We do not know.

Adverse Effects Table:

We do not know…

• Duration of protection.
• Effectiveness against transmission.
• Vaccine effectiveness against asymptomatic infection Data is limited to assess the effect of the vaccine against asymptomatic infection as measured by detection of the virus and/or detection of antibodies against non-vaccine antigens that would indicate infection rather than an immune response induced by the vaccine.
• Effectiveness or safety among certain high-risk populations, such as children less than 16 years of age, pregnant and lactating individuals, and immunocompromised individuals.
• Benefits of individuals with prior COVID19 infection. But, given there is documented reinfection, the FDA stated that previously infected by people could benefit from vaccination.
• Vaccine effectiveness against long-term effects of COVID-19 disease. COVID-19 disease may have long-term effects on certain organs, and at present it is not possible to assess whether the vaccine will have an impact on specific long-term sequelae of COVID-19 disease in individuals who are infected despite vaccination. Demonstrated high efficacy against symptomatic COVID-19 should translate to overall prevention of COVID-19- related sequelae in vaccinated populations,
• It is possible that asymptomatic infections may not be prevented as effectively as symptomatic infections and may be associated with sequelae that are either late-onset or undetected at the time of infection (e.g., myocarditis).

The AstraZeneca adenoviral chAdOx1Cov-190 vaccine

• AstraZeneca adenoviral ChAdOx1 nCoV-190 vaccine trial was published in the Lancet 0n 09/12/2020/ Published Online December 8, 2020. https://doi.org/10.1016/ S0140-6736(20)32623-4.
• The ChAdOx1 nCoV-19 vaccine (AZD1222) was developed at Oxford University. It consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene.
• After phase 1 results supported a two-dose regimen, the trial protocols were amended where necessary to require two standard doses of approximately 5×10¹⁰ viral particles per dose administered 28 days apart.
• Participants randomly received either the ChAdOx1 nCoV-19 vaccine or control, which was either meningococcal conjugate vaccine (MenACWY) or saline depending on the trial.
• It is based on cases occurring within approximately 4 months of follow-up in 11636 participants (aged 18–55 years).
• Efficacy was similar when evaluated starting at 21 days after the first standard dose, suggesting there is at least short-term protection with one dose.

• Surprisingly, efficacy was substantially lower in the SD/SD cohort (62·1% [95% CI 41·0 to 75·7]; 27 [0·6%] of 4440 vs 71 [1·6%] of 4455) than in the LD/SD cohort (90·0% [67·4 to 97·0]; three [0·2%] of 1367 vs 30 [2·2%] of 1374), which remained after accounting for differences in age and time.

• Overall efficacy of 70% is lower than the 90-95% being reported for mRNA vaccines from Pfizer-BioNTech and Moderna; and from the Russian Sputnik adenoviral vector vaccine.
• Adverse effects:
• No serious adverse events or deaths occurred that were treatment associated in ChAdOx1 nCoV-19 recipients.
• But there were 175 serious adverse events (84 in the ChAdOx1 nCoV-19 group and 91 in the control group), three of which were possibly related to the intervention: transverse myelitis occurring 14 days after a ChAdOx1 nCoV-19 booster vaccination, haemolytic anaemia in a control recipient, and fever higher than 40°C in a participant still masked to group allocation.
• The transverse myelitis cases resulted in temporarily pausing the trial and all participants have recovered or are recovering.
• “Disparity between immunogenicity and efficacy findings could imply that clear-cut immunological correlates of clinical protection might not exist for COVID-19 vaccines, meaning efficacy cannot be extrapolated to other unevaluated ages or populations”- Editorial in Lancet.
• TAKE HOME: AstraZeneca adenoviral chAdOx1Cov-190 vaccine:
  • Good promise for affordable compared with the high cost of the two mRNA vaccines that have reported more than 90% efficacy.
  • ChAdOx1 nCoV-19 has an acceptable safety profile.
  • It has been found to be efficacious against symptomatic COVID-19.
  • The ChAdOx1 nCoV-19 vaccine can also use routine refrigerated cold chain, which is important since the ultra-low temperature freezers required to store mRNA vaccines could be unaffordable and impractical in many countries

Moderna Vaccine

• Moderna’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study. (press release).
• Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics.
• It announced on 16th November 2020 that the independent, NIH-appointed Data Safety Monitoring Board for the Phase 3 study of mRNA-1273, its vaccine candidate against COVID-19, has informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy.
• The vaccine efficacy is 94.5%.
• This study is known as the COVE study.
• The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine.
• This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5% (p <0.0001).
• A secondary endpoint analysed severe cases of COVID-19 and included 11 severe cases in this first interim analysis.
• It is told to be the most promising.
• Adverse events:
  1. Mild or moderate in severity.
  2. Grade 3 (severe) events greater than or equal to 2% in frequency after the first dose included injection site pain (2.7%), and after the second dose included fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%).

Indian Scenario

• Active cases show a “clear-cut declining trend.”
• The government is expecting two vaccines against Covid-19:
  1. Baharat Biotech-Covaxin.
  2. Astra Covishield.
• Both expected to be available by January 4 2021.

COVISHIELD: 

• Pune-based Serum Institute of India has sought approval for its version of the vaccine developed by Oxford University and AstraZeneca.
• The candidate is currently in phase-III trials in India.
• In its application, Serum has submitted the safety data from phase I and phase II trials.
• The effectiveness data has been sourced from phase-III trials of the same vaccine in the UK and Brazil.

COVAXIN: 

• Bharat Biotech, a Hyderabad-based company which is developing a vaccine.
• Covaxin, in collaboration with National Institute of Virology, an ICMR institute in Pune, has started phase-III trials only recently.
• Its application is based mainly on the safety data from phase-I and phase-II trials.

BNT162b2: 

• US pharmaceutical major Pfizer hasn’t carried out clinical trials in India of its vaccine, developed in collaboration with BioNTech.
• It has still sought an approval to use it here based on the results of the trials conducted in the US.
• The Pfizer-BioNTech vaccine is the first one to receive the regulator’s approval anywhere in the world, having been granted emergency use authorisation in the UK last week.

Russia’s SPUTNIK V vaccine

• In India Russia’s SPUTNIK V vaccine is also in human trial. Sputnik V vaccine has been developed by the Gamaleya National Research Centre of Epidemiology and Microbiology and Russian Direct Investment Fund (RDIF).
• As per reports, India has purchased 100 million doses of the candidate from Russia. This vaccine shows 92% efficacy is based on the first interim data from the largest double-blind, randomised, placebo-controlled Phase III clinical trials in Russia involving 40,000 volunteers.
• The findings of the trial are not yet peer-reviewed. The vaccine is being tested on humans in mid- to late-stage trials by Hyderabad-based Dr Reddy’s Laboratories
• There are two forms of the Sputnik V vaccine – liquid, which would have to be stored at minus 18°C and lyophilised (freeze dried), which can be stored at 2°C to 8°C.
• The lyophilised form was developed especially for the transportation of the vaccine to remote places.
• Sputnik V is a human adenovirus vaccine that uses two weakened and genetically modified common cold viruses to carry the code for the cells in the human body to build the Covid-19 spike protein (the spiky outer layer of the SARS-CoV-2 virus).

CME INDIA Learning Points

• Vaccines could play an important role in increasing population immunity, preventing severe disease, and reducing the ongoing health crisis.
• Another lingering question is whether the vaccine is capable of fighting asymptomatic infections; an immunization that could prevent these could be key to shaping the course of the pandemic.  
• The data show that the low-dose vaccine regimen was about 60% effective in reducing asymptomatic infections, but it was unclear whether the standard dose significantly reduced such infections at all.
• The two leading RNA vaccines have not gathered data on asymptomatic infections, but they have been more than 90% effective in preventing symptoms of COVID-19
• The Oxford team is the first among these three leading vaccine developers to publish its results in a peer-reviewed journal — so far. Other 2 vaccine   findings from phase III trials have been disseminated only through press releases.

CME INDIA Tail Piece

1. What is McKeown hypothesis?

• It is well known that for scarlet fever, for tuberculosis, for typhoid, the miracle drugs didn’t bring rampant disease to a sudden end.
• These drugs shut the door for good on outbreaks that had largely died out already.
• McKeown hypothesis — Medical interventions tend to play only a small role compared to public-health measures, socioeconomic advances, and the natural dynamics of the disease as it spreads through a population.
• The country may still reach herd immunity through natural disease spread.
• Worth to ponder -Ineffective vaccine could also give false security to those receiving it, thereby helping spread the disease by providing population-scale license to irresponsible behaviour (indoor parties, say, or masklessness).

2. This is the final minute of CDCSCO meeting on 09.12.2020. This should finish all cluttering:

3. U.A.E. is first to approve Chinese vaccine:  The UAE approved a Chinese coronavirus vaccine after preliminary data showed that it was 86 percent effective. It is the first government to grant approval to the vaccine developed by Sinopharm, a state-owned vaccine maker. The Chinese vaccines could offer a lifeline to developing countries that cannot afford vaccines from the United States that are likely to be more expensive and more difficult to transport. Sinopharm has been running trials in 10 countries, data from which has not yet been released. The experimental coronavirus vaccine is developed by China National Pharmaceutical Group (Sinopharm). In July, the Gulf Arab state started Phase III clinical trials of the vaccine, developed by Beijing Institute of Biological Product, a unit of Sinopharm’s China National Biotec Group (CNBG). In September, it authorised emergency use of the vaccine for certain groups, the first such international clearance for a vaccine developed in China. The analysis also shows “99% seroconversion rate of neutralizing antibody and 100% effectiveness in preventing moderate and severe cases of the disease.

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