Decoding the Magic Number for Vaccine Booster Doses to Combat COVID-19: Why the Race for Developing New SARS-CoV-2 Vaccines Is Far from Over
Ryan Varghese Mathew, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Saint Joseph’s University
Rushil Dalal, Faculty of Biology, Ludwig Maximilian University of Munich
Jainam Karsiya, River Route Creative Group LLP
Dileep Kumar, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University
Since the declaration of the SARS-CoV-2 or COVID-19 outbreak as a global pandemic by the World Health Organization, in March 2020, several prevention and treatment strategies have been devised since then. These prevention and mitigation strategies form a broad spectrum of interventions ranging from plant-based decoctions to potent antiviral drugs. However, the most imperative intervention is the research and development of vaccines and their booster doses. But the question underscoring the ‘Magic Number’ of booster doses that must be administered for conferring optimal immunity still remains a mystery. With several countries commencing a de facto booster vaccination program, the rationale behind vaccination development and administration remains questionable, thereby causing a major public health concern. This article aims to explore and compare recent evidence findings across the world while providing an overview of the vaccination panorama.
Introduction
With the rise in COVID-19 cases at an alarming rate, the need for vaccines and subsequent booster doses is greater than ever. But this begs the question of the 'Magic Number' of booster doses for optimal immunity against the SARS-CoV-2 variants.
Recent shreds of evidence have revealed that an additional third shot or booster dose of vaccines, could benefit the people by providing increased protection, especially against the Omicron variant. Furthermore, some governments have even begun a de facto program to administer the fourth dose of vaccinations. However, this leaves the scientific and medical fraternity perplexed, as endless boosting would not be a viable strategy, defeating the purpose for which vaccines were designed to be used [1].
The preliminary data analysis conducted in Israel concluded that the fourth dose of vaccinations for adults aged 60 and above, raises the protection against the infection by up to 2 times, and other severe ailments by up to 3 times, compared to those previously inoculated with the third-dose of vaccines [2].
Despite this, the question debating the efficacy of the third or fourth dose in conferring prolonged immunity against Omicron and other emerging variants of SARS-CoV-2 remains unanswered. Some researchers opine that this answer would vary with the primary objective of vaccination – whether boosters are administered as prophylaxis to impede the transmission of the virus, or to reduce the severity of the disease [1].
These booster doses could also potentially expand the immune response, to protect against emerging variants [3,4,5,6].
Although in the face of the rising Omicron cases, the booster doses have been administered to elevate the levels of circulating antibodies, these booster doses do not provide prolonged immunity, and often plummet within months [6,7,8].
Based on data published from vaccine trials, Miles Davenport and his colleagues predicted that vaccinated people would lose about half of their neutralizing antibodies in about 108 days. Thus, vaccines that would have promised 90% of protection against mild cases, would confer only 70% protection after 6 or 7 months. This raises a major public health concern, as vaccine-induced antibodies are less effective or even ineffective against emerging SARS-CoV-2 strains, compared to the ancestral strain [9,10,11].
This data was corroborated by the United Kingdom “SIREN” research, which was conducted on the healthcare workers. The study concluded that the prior infection provided 85% protection against a second SARS-CoV-2 infection, in more than 6 months, in the pre-Omicron era. However, recent findings claim that this protection has been significantly reduced to 19% against the Omicron variant [12].
One of the only long-term studies that coherently viewed the three components of the immune system, antibodies, B cells, and T cells, concluded that vaccination elicited lasting cellular immunity. Additionally, Memory B cells, which are associated with the rapid antibody deployment upon re-exposure to the virus, multiplied for at least 6 months and improved their ability to combat the virus over time. Furthermore, the number of T-cells remained fairly constant over the study tenure [9,13].
However, with a third booster dose, these memory B-cells and T-cells remain capable of battling the Omicron variant, reducing the risk of hospitalization and severe illness, despite the plunge in the antibodies [9,13].
Research from the Washington University School of Medicine in St. Louis, Missouri, underscored that germinal centers of vaccinated individuals produced more potent immune cells over time. They have also described these germinal centers to be active for more than 6 months after inoculation with an mRNA-based vaccine, which was longer than any vaccine developed by conventional techniques for any other disease [14].
Real-world evidence obtained from clinical settings in the United States, the United Kingdom, and Israel indicates that the third shot of an mRNA vaccine (mainly administered in the western world) reduced the risk of hospitalization of patients for up to 5 months against the Delta variant and about 3 months against the Omicron variant. This booster dose not only helps restore the antibody levels but also broadens the response against emerging variants [15,16,17].
However, the people immunized with inactivated virus vaccines and live attenuated vaccines (predominantly used in the lower and middle-income countries), such as China’s Sinopharm jabs and CoronaVac, and India’s Covaxin may require two additional doses of the mRNA vaccine as an optimal prophylactic measure against Omicron [18,19].
Analyzing the Real-world evidence from hospital databases has revealed that the elderly people at the start of the year, were at about twice the risk during a July outbreak, compared to those immunized a month before the outbreak [20].
A study in Qatar substantiated the high protective action against severe diseases and the reduced risk of hospitalization after vaccination with a Pfizer-BioNTech vaccine for about six months [20].
Older people administered the third dose of the vaccine were less likely to be infected or develop the severe disease than those who had not received booster doses [9].
Recent research focuses on the pressing need to develop new vaccines that could have a longer, enduring effect while providing adequate protection against both existing and emerging strains of SARS-CoV-2. Various vaccines have been studied as a prophylactic measure to combat the spread of COVID-19 and have been approved for use. However, their long-term implications and efficacy still need to be thoroughly studied.
Conflict of Interest
The authors declare that there is no conflict of interest.
Funding Information
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References
1. Watson C. Three, four or more: what’s the magic number for booster shots? [Internet]. Nature News. 2022 [cited 2023 Mar 24]. Available from: https://www.nature.com/articles/d41586-022-00200-9#ref-CR2
2. Ministry of Health - Government of Israel. Preliminary Data Analysis: Effectiveness of the Fourth Dose for Older Adults 60 Years of Age and Older [Internet]. Ministry of Health Updates. 2022 [cited 2023 Mar 24]. Available from: https://www.gov.il/en/departments/news/23012022-01
3. Corbett KS, Gagne M, Wagner DA, O’ Connell S, Narpala SR, Flebbe DR, et al. Protection against SARS-CoV-2 Beta variant in mRNA Wald A. Booster Vaccination to Reduce SARS-CoV-2 Transmission and Infection. JAMA. 2022;327(4):327–328. doi:10.1001/jama.2021.23726
4. Spitzer A, Angel Y, Marudi O, et al. Association of a third dose of BNT162b2 vaccine with incidence of SARS-CoV-2 infection among health care workers in Israel. JAMA. Published online January 10, 2022. doi:10.1001/jama.2021.23641
5. Rubin R. COVID-19 Vaccine Makers Plan for Annual Boosters, but It’s Not Clear They’ll Be Needed. JAMA.2021;326(22):2247–2249. doi:10.1001/jama.2021.21291
6. Levin EG, Lustig Y, Cohen C, Fluss R, Indenbaum V, Amit S, Doolman R, Asraf K, Mendelson E, Ziv A, Rubin C. Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. New England Journal of Medicine. 2021 Dec 9;385(24):e84.
7. Centers for Disease Control and Prevention. Science Brief: SARS-CoV-2 Infection-induced and Vaccine-induced Immunity [Internet]. 2021. Available from: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/vaccine-induced-immunity.html
8. Dolgin E. COVID vaccine immunity is waning — how much does that matter? [Internet]. Nature News Explainer. 2021 [cited 2023 Mar 24]. Available from: https://www.nature.com/articles/d41586-021-02532-4
9. Khoury, D.S., Cromer, D., Reynaldi, A. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 27, 1205–1211 (2021). https://doi.org/10.1038/s41591-021-01377-8
10. Pegu A, O’Connell SE, Schmidt SD, O’Dell S, Talana CA, Lai L, Albert J, Anderson E, Bennett H, Corbett KS, Flach B. Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants. Science. 2021 Sep 17;373(6561):1372-7.
11. Head E, Elsland DSL van. Omicron largely evades immunity from past infection or two vaccine doses [Internet]. Imperial College London Health News. 2021 [cited 2022 Mar 24]. Available from: https://www.imperial.ac.uk/news/232698/omicron-largely-evades-immunity-from-past/
12. Goel RR, Painter MM, Apostolidis SA, Mathew D, Meng W, Rosenfeld AM, Lundgreen KA, Reynaldi A, Khoury DS, Pattekar A, Gouma S. mRNA Vaccination induces durable immune memory to SARS-CoV-2 with continued evolution to variants of concern. Biorxiv. 2021 Jan 1.
13. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, O’Halloran JA. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature. 2021 May 24:1-5.
14. Barda N, Dagan N, Cohen C, Hernán MA, Lipsitch M, Kohane IS, Reis BY, Balicer RD. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. The Lancet. 2021 Dec 4;398(10316):2093-100.
15. Andrews N, Stowe J, Kirsebom F, Toffa S, Sachdeva R, Gower C, Ramsay M, Bernal JL. Effectiveness of COVID-19 booster vaccines against covid-19 related symptoms, hospitalisation and death in England. Nature medicine. 2022 Jan 14:1-.
16. Arbel R, Hammerman A, Sergienko R, Friger M, Peretz A, Netzer D, Yaron S. BNT162b2 vaccine booster and mortality due to Covid-19. New England Journal of Medicine. 2021 Dec 23;385(26):2413-20.
17. Garcia-Beltran WF, Denis KJ, Hoelzemer A, Lam EC, Nitido AD, Sheehan ML, Berrios C, Ofoman O, Chang CC, Hauser BM, Feldman J. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022 Jan 6.
18. Bharat Biotech. Fact Sheet for Vaccine Recipients & Caregivers [Internet]. 2021 [cited 2022 Mar 24]. Available from: https://www.bharatbiotech.com/images/covaxin/covaxin-factsheet.pdf
19. Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman LS, Haas E, Milo R, Alroy-Preis S, Ash N, Huppert A. Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel. MedRxiv. 2021 Jan 1.
20. Chemaitelly H, Tang P, Hasan MR, AlMukdad S, Yassine HM, Benslimane FM, Al Khatib HA, Coyle P, Ayoub HH, Al Kanaani Z, Al Kuwari E. Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar. New England Journal of Medicine. 2021 Dec 9;385(24):e83.
Ryan Varghese is a researcher affiliated with the Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, and Philadelphia, USA. His work spans a spectrum of topics from artificial intelligence to cancer theranostics and drug delivery in Alzheimer's disease. His specialization lies in the drug delivery modalities in chronic diseases. He has curated several articles on the lacunae in the Government’s public policies while providing solutions for the same. His recent work included the proposal on drug repurposing and affordable hospitalization to mitigate the risk stemming from COVID-19 in India. His current line of work lies in the efficient diagnosis and treatment of various cancers.
Rushil Dalal is a researcher currently affiliated with the Ludwig-Maximilians-Universität München. With a formal education in Biotechnology, his current lines of work encompass the development of novel therapeutics for oncological malignancies. Previously, he was associated with the Tata Memorial Centre - Advanced Centre for Treatment, Research and Education in Cancer (TMC-ACTREC). During his tenure, he has contributed significantly to the Department of Clinical Pharmacology, with his research in oncogenomics, where he was on the quest to elucidate SNPs that amplified the occurrence of tobacco-related head and neck cancer.
Jainam Karsiya is a clinical pharmacist and medical affairs executive associated with RiverRoute Creative Group, India. His domain of work expands across the length and breadth of oncology, ranging from drug delivery and clinical therapeutics to precision oncology. He has prior experience in nanotechnology, theranostics, and health outcomes research. He has also contributed to the drafting of public policies in the healthcare sector.
Dileep Kumar is an associate professor in the Department of Pharmaceutical Chemistry at Poona College of Pharmacy. He is a pioneer in his field with his forte in the treatment and novel drug delivery in Cancer and Alzheimer’s disease, especially adamantyl analogs as GluN2B selective NMDA receptor agonists. He is also an awardee of the Junior Research Fellowship from the National Medicinal Plant Board (NMPB) New Delhi, a Senior Research Fellowship from the University Grants Commission (UGC), a Teaching Assistantship, and an Institute Post-Doctoral Fellowship from IIT (BHU) Varanasi. He is the Guest Editor of prestigious journals like Current Topics in Medicinal Chemistry, Current Drug Target, combinatorial chemistry, and Molecules.
