CME INDIA Presentation by Dr. Rajeev Jayadevan, MD, DNB, MRCP, ABIM (Med) ABIM (Gastro), NY. Vice Chairman, Kerala state IMA Research Cell. Member, National IMA Task Force on Corona Epidemic, Cochin.

While news of waning vaccine-induced immunity against COVID-19 have begun to make waves, few new studies are trying to explore the unknown sea. One study which appeared on medRxive on 25th August 2021 (Not peer-reviewed) demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.” (1)

However, findings from such studies must be reviewed very carefully for implications.

Natural Immunity Vs Vaccine-Induced Immunity

Pfizer effectiveness dropped to 6% at 4.5 months

Two important studies:

Study 1:

  • A large study from Israel compared 3 groups of people:
    • Past infection
    • Pfizer-vaccinated individuals
    • Those who had both
  • Large cohort of 673,676 vaccinated, 62883 past infection, & 42,099 vaccinated who also had past infection. The groups were matched to exclude confounding.
  • They looked at remote & recent past infection separately. Those who were infected in 2021 had greater protection than 1 year ago.
  • The vaccinated group had a 27-fold greater risk of SYMPTOMATIC breakthrough infection compared to natural infection. The risk was 13-fold for ALL breakthrough infections.
  • A single dose of vaccine further increased the level of protection for those who had past infection.
  • Those who were infected a year ago (2020) still had better protection than vaccination, (but the difference was lower than 2021 infection); this was 7-fold.
  • The protection included symptomatic disease as well as hospitalisation.
  • The study is a direct comparison between natural infection and vaccination.
  • CAUTION: However, this should not be misinterpreted that natural infection is “preferable” to vaccination. That is because the risk of complications with natural infection is far greater than vaccination.

What to Infer?

  1. Those who had natural infection can expect a greater protection against future COVID-19, including against hospitalisation.
  2. Those with natural infection who had a single dose of vaccine enjoyed greater degree of protection.

However, Some Caveats

  • This does not mean or imply that those who are not vaccinated should “wait to be naturally infected” and refuse vaccination.
  • The above is a potentially dangerous conclusion that could arise from not properly understanding the study, particularly if an older person decides to “wait for natural infection” rather than get vaccinated.

Here Is Why

  • It was shown earlier that age is the most significant risk factor for severe disease in COVID-19, far more than comorbidities- still a relatively unknown fact.
  • Thus, a 75-year-old with COVID-19 is at least 200 times more likely to die than a 25-year-old with COVID-19.
  • Besides, the risk of complications of natural infection is far greater than that of vaccination.
  • Vaccine related complications are extremely rare: about 1 in 25,000 (Pfizer) to 1 in 100,000 (covishield). (*In comparison, risk of death as a result of pregnancy is 1:1000 in India, this is considered very rare)

Important to Look into Again

  • For those who are not yet naturally infected, vaccination is the best option.
  • A single dose of vaccine is definitely helpful for those with past infection (anamnestic response)

What is Anamnestic response?

  • If there was exposure to antigen in the past, a 2nd exposure (after a time-gap) will result in a hugely amplified immune response.
  • This is the reason why 2 doses of vaccines are given.
  • The same applies to vaccination after natural infection.
  • Mechanism of anamnestic response:
    • Memory cells made following the 1st infection (or vaccine dose) are already primed & ready for a coordinated immune response by the time the 2nd dose arrives.
    • Memory cells work like amplifiers and also undergo ‘self-improvement’ over time through somatic hypermutation and affinity maturation.
    • No study is without limitations. In this case, a potential confounder is the so-called Peltzman effect (vaccinated people might take more risks, socialise more without masks, and pick up more infections – while unvaccinated people might be more careful).

Limitations to Ponder

  • The study did not address “boosters.” There is no evidence at this time that a 3rd dose will increase protection against severe disease.
  • 3rd dose will transiently increase antibody level, but does not enhance memory cells. Thus, T cell immunity might not be “boosted.”

Study 2:

  • Pfizer vaccine effectiveness drops steeply past 3 1/2 months to 39.6% and to 6% in 4 1/2 months.
  • Protection against severe disease did not decline.
  • The study concludes: “This study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.” (2). Posted on 22nd August 2021.

CME INDIA Learning Points

  • Studies show that convalesced seropositive individuals have approximately 90% protection from SARS-CoV-2 reinfection.
  • The effectiveness of vaccination has been reported as 50 – 95%.
  • Ariel Israel, Yotam Shenhar et al in a large study has shown that among never infected individuals who received the Pfizer-BioNTech mRNA vaccine, higher initial antibody levels followed by a faster decrease rate when compared to patients who had been infected with the SARS-CoV-2 virus.
  • The proportion of vaccinated individuals whose antibody levels drop below the threshold thought to be protective is increasing substantially by the fifth month as per this new study (2).
  • Such drop is uncommon in convalescent individuals.
  • Studies by Tong et al., 2021 and Turner et al., 2021a.  demonstrated that antibodies could be detected up to 11 months after infection and provided evidence that that these antibodies originated in memory B cells, not plasmablasts.
  • Generation of SARS-CoV-2 memory B cells is likely necessary for long-term protection.
  • We are at present in learning curve about the long-term protection provided by the vaccine.


1. Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections.Sivan Gazit, Roei Shlezinger, Galit Perez, Roni Lotan, Asaf Peretz, Amir Ben-Tov, Dani Cohen, Khitam Muhsen, Gabriel Chodick, Tal Patalon medRxiv 2021.08.24.21262415; doi:

2. Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection.Ariel Israel, Yotam Shenhar, Ilan Green, Eugene Merzon, Avivit Golan-Cohen, Alejandro A Schäffer, Eytan Ruppin, Shlomo Vinker, Eli Magen medRxiv 2021.08.19.21262111; doi:

3. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, O’Halloran JA, Presti RM, Ellebedy AH. 2021a. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature 595:421–425. doi:10.1038/s41586-021-03647-4 4.

4. Tong P, Gautam A, Windsor IW, Travers M, Chen Y, Garcia N, Whiteman NB, McKay LGA, Storm N, Malsick LE, Honko AN, Lelis FJN, Habibi S, Jenni S, Cai Y, Rennick LJ, Duprex WP, McCarthy KR, Lavine CL, Zuo T, Lin J, Zuiani A, Feldman J, MacDonald EA, Hauser BM, Griffths A, Seaman MS, Schmidt AG, Chen B, Neuberg D, Bajic G, Harrison SC, Wesemann DR. 2021. Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike. Cell. doi:10.1016/j.cell.2021.07.025

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