CME INDIA Presentation by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh, India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.

“It must also be emphasized that, based on current evidence from longitudinal studies, routine surveillance and observational vaccine effectiveness studies, a primary course of vaccination remains the most efficient way to limit the disease burden and impact of COVID-19. COVID-19 vaccines continue to be very protective against severe disease, hospitalisation and death after completion of primary series and administration of the first booster dose” – EMA’s COVID-19 task force (ETF) and the European Centre for Disease Prevention and Control (ECDC) on 6th April 2022.

Israel and US have started propagating the idea of 4th dose of Covid vaccine or so called second booster. And many nations in Europe have followed. Joe Biden taking the 4th dose has fuelled the fire.

Where do we India stands in relation to this new idea?

• Let’s first analyse how America and Europe decided to opt for a repeat booster?
• In the past month of March 2022, many countries in Western Europe have seen a significant 2nd Omicron wave attributable to the BA.2 variant, and some of them were accompanied by a substantial rise in hospitalizations and deaths. Denmark, Netherlands and Austria had particularly more pronounced BA.2 wave superimposed over BA.1
• BA.2 wave has led to a fresh surge in the number of deaths in Austria, UK, Italy and Belgium – causing panic and rethink.

Who tossed the idea of Second Booster?

• As previously, Israel has been the pioneer for Second Booster as well. There are only 3 studies of the 2nd booster to date. All these were initiated back in December 2021 for people age 60+ during the Omicron wave in Israel. Initially studies were started for immunocompromised but now boosters are administered broadly to all adults who have completed 4 months from their 3rd shot.
• The first small study looked at safety, antibody formation and vaccine effectiveness in preventing infections in health care workers. While the neutralizing antibody response from the 4th shot was good, the effectiveness vs symptomatic infections was quite low, only 31% for Moderna and 44% for Pfizer.
• The second study was in a million people age 60+ with either a 4th dose of at least 4 months out from the 3rd dose (1st booster). Follow-up was only 12+ days but a >4-fold protection against severe disease was demonstrated.
• The most important, 3rd study, was performed at Clalit Health, one of the 4 large healthcare organizations in Israel. It was also among people age 60+ and showed a 78% reduction of death for 4 shots vs 3 shots (post 4 or more months).
• This is remarkably similar to the Clalit Health report in people age 50+ with their first booster compared both only 2 shots (> 4 months out) for whom there was a 90% reduction of mortality.
• Note that the absolute reductions in death are pretty small in these studies (Y-axis), but the huge number of people in these age groups may translate into an important benefit at the population level.

See figure:

For whom does FDA recommend 4th Shot?

• FDA that 4th shots (Pfizer and Moderna) to be provided for people age 50+ as an option.
• Some Experts recommend Second booster to people who are more than 4-6 months from 3rd shot, you are age 50+, who tolerated the previous shots well, and who are concerned about the BA.2 as per risks of their profession or BA.2 spread

Ex FDA Dep Director speaks out against unnecessary boosters.

• Dr Krause who is presently consultant to the World Health Organization and who had been deputy director of FDA’s Office of Vaccines Research and Review, 2011-21 is much against offering booster to general population.
• If you’ve had two doses of vaccine, you have a lot of protection against severe Covid. Likewise, if you’ve been infected with the virus, including with Omicron. If you’re over 65 or otherwise at high risk of severe disease, it’s reasonable to get a third dose. A fourth dose is already authorized for the immunocompromised.
• For everyone else, the data haven’t shown meaningful benefit of three doses, never mind four.
• Vaccine-induced protection against ‘infection’ is short-lived and doesn’t get much of a boost from extra shots. Yet the initial two-dose regimen is enough to provide most patients excellent protection against severe disease-mediated by durable cellular responses, not the neutralizing antibodies that rise and wane quickly after vaccination.

Indian Scientists Dissects Deep into Israel study.

• Dr Rajeev Jayadevan from Kochi dissected deep into the Israeli study to dig out the truth. He made startling observations “Israel 4th dose study has been reported in an exaggerated manner by several media (and western ‘Twitter celebrities’)”
• His chief observations are:

• They studied people over average age 70. This is important, as severe COVID outcomes are more likely occur in this age segment. However, deaths were very very rare in both 3 and 4 dose groups.
• He further points that. “When we look at raw numbers, it is clear there is no difference between the 3 or 4 dose groups”.
• There was a HIGH RATE OF INFECTION, even after three doses of vaccination
• This is a very important finding, up to 22.9% of tests were positive. This shows that boosters, even 3 doses – were not protecting against infection adequately during Omicron wave.
• And this crucial point is not even mentioned in the study results.
• The infection rate in the 4-dose group was less than 3 dose. This makes sense- because in the initial 10 weeks following a vaccine dose, there is a protective window of neutralising antibodies. Unfortunately, with every additional dose, this window gets smaller. This is called the principle of diminishing returns.
• Authors report the additional protective effect of 4th dose (against infection) dropped to 29% in only one and half months.
• He goes on to say that the study tries to hide the truth behind statistical jargon.
• “If we tortured data long enough, it will confess to anything we want.”

Do we need 4th dose Booster in India? 

• It is noteworthy that several countries like India, Bangladesh, and Sweden slowly transitioned to ~100% BA.2 without experiencing increase in cases nor deaths.
• Better protection among Indians can be attributed to higher run through infection by Delta during second wave, better vaccination coverage among vulnerable age groups, superior efficacy of vector-based vaccines and Killed Virus vaccines in providing long term protection and immunity or a combination of these factors.
• Positivity Rate in India is presently 0.2%. Third dose booster is making advances in 60+ slowly. To call for 4th dose booster in India makes no sense except blindly copying the West.
• Nevertheless, the virus is as unpredictable as it is formidable. It may evolve further. So, we need to keep a close watch and act as and when required.

CME INDIA Tail Piece

“Administration of a fourth dose of mRNA vaccines to immunocompromised individuals whose immune system may have mounted a suboptimal response to earlier vaccination is already recommended and should be part of current vaccination campaigns. There are currently no data on immunogenicity, safety or effectiveness of additional further doses in this population. Additionally, in severely immunocompromised subjects, passive immunisation with monoclonal antibodies should be considered as an additional shield to protect against infection and disease.”

References:

1. ECDC. https://www.ecdc.europa.eu/en/covid-19/country-overviews 2 EuroMOMO. https://www.euromomo.eu/bulletins/2022-12/ 3 ECDC Vaccine Tracker
2. Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021| Eurosurveillance
3. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel
4. NEJM 7 BNT162b2 Vaccine Booster and Mortality Due to Covid-19 | NEJM
5. https://cmeindia.in/has-israels-4th-dose-study-been-exaggerated/
6. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/media-resources/science-in-5/episode-26—vaccine dosage?gclid=EAIaIQobChMInZHg_fWL9wIVHMWWCh30xA8SEAAYASAAEgIEU_D_BwE

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