Le Infezioni in Medicina, n. 4, 643-647, 2021

doi: 10.53854/liim-2904-20


Global implication of booster doses of COVID-19 vaccine

Shekhar Kunal1, Ishita Ray2, Pranav Ish3

1Department of Cardiology. ESI Faridabad, Haryana, India;

2Mahatma Gandhi Memorial Medical College, Indore, Madhya Pradesh, India;

3Department of Pulmonary and Critical Care Medicine, VMMC and Safdarjung Hospital, New Delhi, India

Article received 13 November, 2021; accepted 21 November, 2021

Corresponding author

Pranav Ish

E-mail: pranavish2512@gmail.com

To the Editor

The emergence of highly transmissible novel COVID-19 variants such as the delta (B.1.617.2) has sparked worldwide fear leading to the consideration for booster doses of COVID-19 vaccines in previously vaccinated individuals. COVID-19 booster doses refer to the extra doses of the vaccine needed to increase the immunity of healthy individuals who have completed their primary vaccination series.

The rationale: Administration of the booster dosage can either be homologous with the same vaccine used as in primary series or heterologous wherein a completely different vaccine platform is used for boost immunizations and prevent development of immune escape [1]. Additionally, emergence of newer variant(s) of concern (VOCs) such as the delta poses further challenges owing to immune escape. Such had been the case with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine which was developed against the original strain of COVID-19 and had lower neutralization efficacy against the delta variant [2, 3]. Moreover, additional doses of COVID-19 vaccine are also warranted in specific population groups such as elderly population. Data from a retrospective study in Israel revealed that nearly 40% of the breakthrough infections occurred in immunocompromised individuals [4]. Similarly, estimates from the Centers for Disease Control and Prevention (CDC) suggest that 66% of hospitalization and 85% of deaths following breakthrough infections in fully vaccinated individuals occurred in people aged ≥ 65 years [5]. Lastly, a heterologous booster dose of a m-RNA vaccine with a high protective efficacy against novel variants such as delta might be needed for countries which have initially utilized an inactivated-virus vaccine for primary vaccination. United Arab Emirates (UAE), Bahrain and Philippines advocate a booster dose with m-RNA vaccine as Sinopharm vaccine with a low protective efficacy against Delta was administered during the early phases of vaccination [6].

The flip-side: There is evidence regarding the waning of protective efficacy, but that does not necessarily mean increased predisposition to infection as cell mediated immune response and the memory B and T-cells have a critical role in developing a long-lasting immunity. Vaccines which were developed in the initial phases of the pandemic might not be equally efficacious against all the COVID-19 variants. This was reflected in data from the Unites States (US) as well as Israel wherein vaccines had a lower efficacy in preventing breakthrough or reinfections [4, 7]. Estimates from the CDC report that among 189 million people vaccinated against COVID-19, only 41,127 patients (0.02%) had breakthrough COVID-19 infection leading to hospitalization or deaths [5]. Additionally, during the recent surge of the Delta variant of COVID-19 in the US as compared to vaccinated individuals, unvaccinated ones had six times higher risk of infection and eleven times greater risk of death [7]. Lastly, we cannot unsee the possibility of increased immunological adverse effects of COVID-19 vaccines such as myocarditis (mRNA-based vaccines) or Guillain-Barre syndrome (adenovirus-vectored vaccines) [8, 9].

The Evidence: Currently, there is limited data regarding the real-world effectiveness of administration of booster doses. Much of this is derived from a study from Israel where booster (third) doses of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) have been approved for individuals >60 years of age in July 2021. This study evaluated 11,37,804 fully vaccinated individuals over a period of one month and reported lower rates of confirmed COVID-19 infection (reduced by a factor of 11.3 [95% CI: 10.4 to 12.3]) and severe illness (reduced by a factor of 19.5 [95% CI: 12.9 to 29.5]) in the booster group as compared to the non-booster group after at least 12 days of vaccination [10]. However, observation studies such as these might be limited by multiple biases such as those of confounding variables or due to behavioral changes adopted following booster vaccination. In addition, the follow-up was short and little is known about the duration of the protective response of the booster doses. Recently, Pfizer and BioNTech SE reported the results of the first phase 3 RCT evaluating efficacy and safety of booster dose of the Pfizer-BioNTech m-RNA based COVID-19 vaccine in over 10,000 individuals aged 16 years and above. In this trial, the relative vaccine efficacy among patients receiving the booster dose was 95.6% (95% CI: 89.3-98.6%) as compared to those receiving a placebo with similar adverse event profile as previous trials on the same vaccine [11].

Global perspective: On 30th July, 2021, Israel became the first country in the world to announce the administration of a third dose of the BNT162b2 vaccine to all individuals >60 years of age who have completed the primary vaccination series at least five months earlier with the aim to reduce the burden on the health care systems. Subsequent recommendations by the CDC, National Health Service (NHS) and Australian Technical Advisory Group on Immunization (ATAGI) allowed administration of the third (booster) dose (Table 1) [12-14].

Recommendations for a booster dose by developed countries can have a boomerang effect on other countries leading to a demand supply imbalance and further hampering the global vaccination rates. This situation becomes worse in Sub-Saharan countries with extremely poor rates of vaccination attributed to limited vaccine availability in these resource limited countries (Figure 1A and 1B). This is in stark contrast to the situation in developed countries such as the US and UK where 56.8% and 66.9% of the population is fully vaccinated respectively [15]. Advocation of booster doses in these developed countries would further hamper vaccination in resource poor countries (Figure 1C and 1D). There is a great disparity among the vaccine statistics in developed and developing nations. This calls for vaccine equity among WHO member states with a need to prioritize vaccinations among the marginalized sections of the society as unvaccinated individuals contribute to the further spread of infection and triggering emergence of newer variants. The recommendations of WHO in order to stop this ravaging pandemic is to vaccinate 40% of individuals in every country by the end of 2021 and to achieve a vaccination target of at least 70% by the first half of 2022 (Figure 1E) [16]. This would require around six billion doses just to vaccinate low-and-middle income countries, the same number of doses administered globally up till now. In order to ensure equitable access to the vaccines across the globe and to prevent vaccine hoarding, a joint endeavor between WHO, GAVI, the Vaccine Alliance, and the Coalition for Epidemic Preparedness Innovations termed COVAX was launched. However, this initiative has not yet helped in achieving its aim of vaccination of the people in poor countries which do not have resources for vaccine manufacture or its purchase from the global market (Figure 1F).

Conclusion: The current evidence and need for booster doses of COVID-19 is still unclear with the current vaccines offering considerable protection against severe disease, hospitalization and death even with newer variants such as the delta. It is reasonable and likely that booster doses of COVID-19 akin to that of influenza vaccines would be needed in future. However, the current focus should be on ramping up the global vaccine supply for greater coverage in the marginalized population groups who have yet not received the first dose of any vaccine.


We certify that we have received no funding for the creation of this work and have no disclosure of other sources of funding that would conflict with the published work.

Conflict of interest

We certify that we have no primary or secondary competing interests or conflicts of interest in submitting and publishing this work.

Ethical approval

The submitted work does not contain human subjects research and is composed of review of the available literature and suggestions to improve clinical practice. The authors certify that there are no ethical conflicts that would preclude its publication.


PI and SK were involved in Conceptualization, literature search. PI, SK and IR were involved in writing, review and editing. All authors have read and agreed to the final draft submitted.


[1] Zhang J, He Q, An C, et al. Boosting with heterologous vaccines effectively improves protective immune responses of the inactivated SARS-CoV-2 vaccine. Emerg Microbes Infect. 2021; 10, 1598-1608. doi: 10.1080/22221751.2021.1957401.

[2] Kunal S, Sakthivel P, Gupta N, Ish P. Mix and match COVID-19 vaccines: potential benefit and perspective from India. Postgrad Med J. 2021 Jul 22: postgradmedj- 2021-140648. doi: 10.1136/postgradmedj-2021-140648.

[3] Kunal S, Aditi, Gupta K, Ish P. COVID-19 variants in India: Potential role in second wave and impact on vaccination. Heart Lung. 2021; 50 (6), 784-7. doi: 10.1016/j.hrtlng.2021.05.008.

[4] Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect. 2021; S1198-743X(21)00367-0. doi: 10.1016/j.cmi.2021.06.036.

[5] COVID-19 Vaccine Breakthrough Case Investigation and Reporting. CDC. Available at: https://www.cdc.gov/vaccines/covid-19/health-departments/breakthrough-cases.html. Accessed on 24th October, 2021.

[6] Bourla A. Countries using AstraZeneca, Chinese vaccines are considering boosters for Delta protection. ThePrint. 9th July, 2021. Available at: https://theprint.in/health/countries-using-astrazeneca-chinese-vaccines-are-considering-boosters-for-delta-protection/692735/. Accessed on 24th October, 2021.

[7] Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021; 385 (16), 1474-84. doi: 10.1056/NEJMoa2109072.

[8] Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 Vaccination in a Large Health Care Organization. N Engl J Med. 2021: NEJMoa2110737. doi: 10.1056/NEJMoa2110737.

[9] Min YG, Ju W, Ha YE, et al. Sensory Guillain-Barre syndrome following the ChAdOx1 nCov-19 vaccine: Report of two cases and review of literature. J Neuroimmunol. 2021; 359, 577691. doi: 10.1016/j.jneuroim.2021. 577691.

[10] Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021; 385, 1393-400. doi: 10.1056/NEJMoa2114255.

[11] Pfizer and BioNTech Announce Phase 3 Trial Data Showing High Efficacy of a Booster Dose of Their COVID-19 Vaccine. October 21, 2021. Available at: https://www.businesswire.com/news/home/202110 21005491/en/. Accessed on 22nd October, 2021.

[12] COVID-19 Vaccine Booster Shots. CDC. 27th October, 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html. Accessed on 28th October, 2021.

[13] Coronavirus (COVID-19) booster vaccine. NHS. Available at: https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-booster-vaccine/. Accessed on 22nd October, 2021.

[14] Australian Technical Advisory Group on Immunization (ATAGI) recommendations on the use of a booster dose of COVID-19 vaccine. 27th October, 2021. Available at: https://www.health.gov.au/resources/publications/atagi-recommendations-on-the-use-of-a-booster-dose-of-covid-19-vaccine. Accessed on 28th October, 2021.

[15] Ritchie H, Mathieu E, Rodés-Guirao L, et al. Coronavirus Pandemic (COVID-19). 2020. Published online at OurWorldInData.org. Available at: https://ourworldindata.org/covid-vaccination-global-projections. Accessed on 29th October, 2021.

[16] WHO, UN set out steps to meet world COVID vaccination targets. 7th October 2021. Available at: https://www.who.int/news/item/07-10-2021-who-un-set-out-steps-to-meet-world-covid-vaccination-targets. Accessed on 22nd October, 2021.