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.

The Science and Art of Booster Doses

COVID Vaccine: Waning Immunity and Booster shots

Doctors pitching for a booster shot in India

  • President Joe Biden taking 3rd does booster has set the stage for a booster shot.
  • Just the fact that Pfizer boosters are now available to certain high-risk groups is taken as a big sign that boosters for other COVID-19 vaccines aren’t far behind and that could be  strong indicator that they will be made available to the rest of the population soon.
  • Some doctors had been pitching for a booster shot in India as well, maybe at least for Front Line workers.
  • But, it is to be emphasised that boosters are not for everyone. And ICMR has categorically denied any possibility of a third dose booster in India, at least for now.
  • Data on Boosters mainly comes from Pfizer Vaccine and can’t be extrapolated to other vaccines worldwide. Not even for other mRNA vaccines.
  • Considering risks of immune side-effects like myocarditis with mRNA vaccines – FDA is planning to approve only half dose of Moderna as the booster dose.

CDC, too, has been very selective for recommending boosters for the needy

  • CDC has said One can get a Pfizer booster if you received the Pfizer vaccine and are a part of one of these groups:
    1. 65 years old or older.
    2. 18 years old or older and at high risk for severe COVID-19.
    3. If you work or live in a situation that puts you at high risk for severe COVID-19. For example, health care workers, teachers, and people in prisons and homeless shelters.

FDA too clears the Air

  • Biden administration last month had announced plans to give boosters to nearly everybody. But U.S. regulators rejected the across-the-board approach and instead said third shots of Pfizer’s vaccine should go to people who are 65 and older and sure others at high risk from COVID-19.
  • For those who have received the Pfizer and Moderna, FDA has said that people with weaker immune systems or those who went through transplant or those with certain cancers/ disorders can get the third vaccine booster shot at least 28 days after receiving the second dose of vaccine.
  • It is noteworthy that Johnson & Johnson vaccine recipients in the USA have not been recommended to take a booster dose.
  • Booster dose for the general population entails many risks without substantial added benefits. So boosters are best left for select groups.

Risks of Boosters – Not as safe as Primary Vaccination!

  • It is established that the benefits of primary COVID-19 vaccination clearly outweigh the risks, but there could be problems if boosters are widely introduced too soon or too frequently, especially with vaccines that can have immune-mediated side-effects (such as myocarditis, which is more common after the second dose of some mRNA vaccines).
  • Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines.
  • Unnecessary boosters to masses causing significant adverse reactions, could have implications for vaccine acceptance.
  • In a country like India, where only 68% of adults have received primary vaccination. It is more important to vaccinate a a larger population with primary vaccination rather than select classes with boosters. Current vaccine supplies could save more lives if used in previously unvaccinated populations than if used as boosters in vaccinated populations.
  • It is doubted that boosters will work in subjects with primary vaccination failure. Though booster dose can augment the immune response from low to high, in grossly immunocompromised individuals, the booster may not kick start the formation of antibodies from zero.
  • Nevertheless, people with a poor immune response like old age, co-morbid conditions, immunosuppressive treatment could be good candidates for boosters.  However, widespread boosters should be undertaken only if there is clear and appropriate evidence.
  • Are studies promoting boosters Booster doses unbiased?
  • Most of the observational studies forming the basis of conclusion are preliminary and challenging to interpret precisely due to potential confounding and selective reporting. Careful and public scrutiny of the evolving data will be needed to assure that decisions about boosting are informed by reliable science more than by politics.
  • How much profit do Pharma companies make from Boosters?
  • Most of the vaccinations so far in the U.S. have come from Pfizer and Moderna. They have inoculated about 99 million and 68 million people, respectively. Johnson & Johnson is third with about 14 million people.
  • It is expected boosters alone to bring in about $26 billion in global sales next year for Pfizer and around $14 billion for Moderna – if they are endorsed for nearly all Americans.
  • The boosters could be more profitable than the initial doses because they won’t come with the research and development costs the companies incurred to get the vaccines on the market in the first place.
  • If Pharma companies are successful in pushing a yearly booster in the name of new variants,  it could make the vaccines a major recurring source of revenue.
  • Science has a dark and dingy dangerous side too. So watch out and tread your path cautiously.

International studies on Boosters:

Data on Booster dose comes mainly from Israel and USA.


  • Israel began administering boosters in late July to people over 60, giving scientists more time to examine their ability to combat Covid and bolster the waning effectiveness of the initial series of doses. 
  • National Institutes of Health Director Dr. Francis Collins called Israel’s data on Covid-19 booster shots “impressive,” noting that the shots provided a tenfold reduction in infection within 12 days after that booster, and also a reduction in severe illness, which is the thing we’re most concerned about, for people who received a third dose of the Pfizer-BioNTech vaccine.

COVID Vaccine: Waning Immunity and Booster shots
Reduction in Rate of Confirmed Infection in Booster Group as Compared with Nonbooster Group.

Conclusions (5)

In this study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, we found that the rates of confirmed Covid-19 and severe illness were substantially lower among those who received a booster (third) dose of the BNT162b2 vaccine.

COVID Vaccine: Waning Immunity and Booster shots
COVID Vaccine: Waning Immunity and Booster shots


Summary-balance of benefits and harms for booster doses

  • Data from clinical trial limited in size (n~300) and age (primarily 18-55 years)
  • Booster dose of Pfizer-BioNTech COVID-19 vaccine increases immune response in those who have completed the primary series approximately 6 months previously
    • Individual benefit/risk balance varies by age..
    • Largest benefit from vaccination of individuals more than 65 years of age.
  • Benefit to other ages incrementally smaller, given higher Vaccine Efficacy is maintained from primary series
  • Even within age categories, likely variation within balance of benefits and risks given risk of exposure, medical condition and sex.
COVID Vaccine: Waning Immunity and Booster shots
Source: CDC

Adverse effects to 3rd dose

  • Risk of lymphadenopathy is more after 3rd dose.
  • Exact risk of myocarditis is not known. But nearly 40000 people having received the 3rd dose booster, CDC says risk and adverse effects of booster  are nearly same as after 2nd dose. Risk of myocarditis remain as 24 cases per million doses.
  • Note: Risk of Vaccine induced Thrombocytopenic Thrombosis (VTT) following Covishield is 1.2 per million doses.
COVID Vaccine: Waning Immunity and Booster shots
Source: CDC


  • Ongoing Booster trials by Bharat Biotech. Results are likely to be out in November.
  • The results of the first Phase  trial, conducted in May at AIIMS Delhi and Patna, were to come in August.(Not yet in Public domain). Meanwhile, for the second trial, final results are expected by November 2021. As per sources recruitments for the phase 2 trials are over. Around 650 volunteers are likely to be part of the trials. The first phase had 175 participants.
  • The trials are aimed at assessing the immunogenicity, safety, reactogenicity and tolerability of the Covaxin booster dose.
  • While the nasal vaccine can be administered as two shots, the company is testing whether combining it with Covaxin gives better results. Thus, this can be used as a mix-and-match with Covaxin to produce a more holistic immune response.
  • Two vaccines have different mechanisms of action and trigger slightly different immune responses.
  • Meanwhile, Bharat Biotech has also finished administering the vaccines for its paediatric trial of Covaxin. Now, it is analysing the data before it can submit it to the regulator for review.
  • It may be good to follow our own data rather than acting in haste.

COVID Vaccine: Waning Immunity and Booster shots

Dr. Sanjay Yadlapalli, USA: As with any other disease, we need to look at (number needed to prevent one hospitalisation) NNT to decide on a value of the booster to prevent one hospitalization.

The NNT is much higher than for the primary series of covid vaccination.

Booster will not make sense from a global health perspective.

CME INDIA Learning Points

  • Data do suggest that neutralizing antibody levels are highly predictive of immune protection from symptomatic Covid infection.
  • It is well evident at present that vaccines that initially offered protection, suppose, 90% protection against mild cases of disease might only be 70% effective after 6 or 7 months. Thus decay of the neutralization titer over the first 250 days immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained.
  • The steady decline of antibody levels among vaccinated individuals is creating a mad rash to get booster doses. The cellular immune responses are much longer lasting and this form of immunity protects us  from disease.
  • Memory B cells, which can rapidly deploy more antibodies in the event of re-exposure to the virus, tend to stick around.
  • In the same tune, T cells also induce immunogenicity. Vaccine induced durable immune memory to SARS-CoV-2 continues to evolve over time.
COVID Vaccine: Waning Immunity and Booster shots
  • As per one study, boosting of pre-existing immunity with mRNA vaccination mainly resulted in a transient benefit to antibody titers with little-to-no long-term impact on cellular immune memory.
  • Antibody decay rates has been similar in SARS-CoV-2 naïve and recovered vaccinees.
  • It suggests that additional vaccine doses will temporarily prolong antibody-mediated protection without fundamentally altering the underlying landscape of SARS-CoV-2 immune memory.
  • This landscape  is characterized by durable memory B and CD4+ T cells even when antibody responses begin to wane. (4)

CME INDIA Tail Piece

COVID Vaccine: Waning Immunity and Booster shots

USA today (CDC)

  • 3 vaccines are currently being administered in the United States.
  • For additional doses of mRNA vaccines in immunocompromised persons, the current recommendations state that the additional dose should be the same product as the primary series – If the product given for the first 2 doses is not available, the other vaccine product may be administered.
  • Evidence reviewed by FDA only evaluated a booster dose of Pfizer-BioNTech vaccine after completion of a Pfizer-BioNTech primary series.
COVID Vaccine: Waning Immunity and Booster shots
Source: CDC


1. Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, Subbarao K, Kent SJ, Triccas JA, Davenport MP. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211. doi: 10.1038/s41591-021-01377-8. Epub 2021 May 17. PMID: 34002089.

2. Naaber, P. et al. Lancet Reg. Health.Eur. (2021)

3. Pegu, A. et al. Science 373, 1372–1377 (2021).

4. mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of ConcernRishi R. Goel, , The UPenn COVID Processing Unit, Ian Frank,  et al. bioRxiv 2021.08.23.457229; doi:

5. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, Mizrahi B, Alroy-Preis S, Ash N, Milo R, Huppert A. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021 Sep 15:NEJMoa2114255. doi: 10.1056/NEJMoa2114255. Epub ahead of print. PMID: 34525275; PMCID: PMC8461568.


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