Archives of Academic Emergency Medicine. 2022; 10(1): e53 REV I EW ART I C L E COVID-19 Vaccines’ Protection Over Time and the Need for Booster Doses; a Systematic Review Omid Dadras1,2, SeyedAhmad SeyedAlinaghi1, Amirali Karimi3, Alireza Shojaei1, Ava Amiri1, Sara Mahdiabadi3, Amirata Fakhfouri4, Armin Razi3, Hengameh Mojdeganlou5, Paniz Mojdeganlou6, Alireza Barzegary4, Zahra Pashaei1, Amir Masoud Afsahi7, Parnian Shobeiri3, Esmaeil Mehraeen8∗ 1. Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran. 2. School of Public Health, Walailak University, Nakhon Si Thammarat, Thailand. 3. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 4. School of Medicine, Islamic Azad University, Tehran, Iran. 5. Department of Pathology, Urmia University of Medical Sciences,Urmia, Iran. 6. School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Department of Radiology, School of Medicine, University of California, San Diego (UCSD), California, USA. 8. Department of Health Information Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran. Received: March 2022; Accepted: May 2022; Published online: 4 July2022 Abstract: Introduction: Controversies existed regarding the duration of COVID-19 vaccines’ protection and whether re- ceiving the usual vaccine doses would be sufficient for long-term immunity. Therefore, we aimed to systemati- cally review the studies regarding the COVID-19 vaccines’ protection three months after getting fully vaccinated and assess the need for vaccine booster doses. Methods: The relevant literature was searched using a combi- nation of keywords on the online databases of PubMed, Scopus, Web of Science, and Cochrane on September 17th, 2021. The records were downloaded and the duplicates were removed. Then, the records were evaluated in a two-step process, consisting of title/abstract and full-text screening processes, and the eligible records were selected for the qualitative synthesis. We only included original studies that evaluated the efficacy and immunity of COVID-19 vaccines three months after full vaccination.This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement to ensure the reliability of results. Results: Out of the 797 retrieved records, 12 studies were included, 10 on mRNA-based vaccines and two on inactivated vac- cines. The majority of included studies observed acceptable antibody titers in most of the participants even after 6 months; however,it appeared that the titers could also decrease in a considerable portion of people. Due to the reduction in antibody titers and vaccine protection, several studies suggested administering the booster dose, especially for older patients and those with underlying conditions, such as patients with immunodeficiencies. Conclusion: Studies indicated that vaccine immunity decreases over time, making people more susceptible to contracting the disease. Besides, new variants are emerging, and the omicron variant is continuing to spread and escape from the immune system, indicating the importance of a booster dose. Keywords: COVID-19;COVID-19 vaccines; Immunity; SARS-CoV-2; Vaccines; Vaccine-preventable diseases Cite this article as: Dadras O, SeyedAlinaghi SA, Karimi A, Shojaei A, et al. COVID-19 Vaccines’ Protection Over Time and the Need for Booster Doses; a Systematic Review. Arch Acad Emerg Med. 2022; 10(1): e53. https://doi.org/10.22037/aaem.v10i1.1582. ∗Corresponding Author: Esmaeil Mehraeen, Department of Health Infor- mation Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran. Postal Code: 5681761351, Tel: +98-45-32426801, Fax: +98-45-32422305, E- mail:es.mehraeen@gmail.com, ORCID: http://orcid.org/0000-0003-4108-2973. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem O. Dadras et al. 2 1. Introduction Since the coronavirus disease 2019 (COVID-19) pandemic spread all over the globe, it has been posing a considerable healthcare crisis by affecting more than 250 million indi- viduals and leading to more than 5 million deaths up un- til now (1). It has also influenced other aspects of life, in- cluding economic, technological, and social aspects. Since COVID-19 is highly contagious,substantial effort is required to curtail the pandemic(2). In this regard, vaccines offer a promising opportunity for fighting the pandemic and have shown considerable efficacy against severe COVID-19 infec- tion, hospitalization, and death (3). Despite the emergence of new variants, the most effective approach to curb the pandemic seems to be mass vaccination and reaching herd immunity against severe acute respiratory syndrome coron- avirus 2 (SARS-CoV-2)(4). The duration of immunity that most vaccines generate against various common infections is limited and developing strong immunity often requires booster doses. The genera- tion of long-term immunity by COVID-19 vaccines and the necessity to administer booster doses for different COVID- 19 vaccines is still a matter of debate. Considering this, it is of great importance to define the duration in which the humoral immune responses are efficient enough against COVID-19 infection (3, 5). Some studies have demonstrated that a few months after the injection of the second dose, the effectiveness of COVID-19 vaccines wanes as antibody levels drop (6, 7). Thus, an addi- tional booster dose may be needed to restore the high level of immunity, especially against new variants, and maintain the equilibrium of the protective humoral immunity and COVID- 19 viral load during exposure. Some groups, including the elderly, are at higher risk of profound IgG decrease over time and thus increased probability of being infected with COVID- 19(8). However, it is intriguing that even after a few months, the effectiveness against severe disease course and hospital- ization is rather sustained (6). In a retrospective cohort study conducted by Tartof et al., participants who were fully vacci- nated showed high immunity against all variants of COVID- 19 up until six months after vaccination, but the immunity had been decreasing over that time (6). However, they re- ported no decreased effectiveness against hospital admis- sions in any age group during the study period. Thomas et al. found 91% protection from Pfizer/BioNTech vaccine after six months, silencing the concerns and showing its sufficient protection during this time (9). On September 17th, 2021, the United States food and drug administration (FDA) refuted the need for a booster dose six months after the second dose of the Pfizer/BioNTech vaccine for the gen- eral population, and only recommended it for people above 65 years of age and some specific groups, but later booster doses were recommended for all the people (10, 11). Concerns still exist regarding vaccines’ duration of immunity and the need for booster doses, especially for other types of vaccines (12). Considering that new variants of COVID-19 may continue to emerge all around the world and disrupt the efforts that have been done so far to control the pandemic, it is of great importance to determine which vaccines require a booster dose for maintaining immunity against COVID-19. A systematic evaluation of this matter elucidates the path for designing new vaccination strategies. Therefore, we aimed to systematically review the studies regarding the COVID-19 vaccines’ protection three or more months after getting fully vaccinated and assess if vaccine booster doses are required. 2. Methods This study is a comprehensive review of the literature to de- scribe COVID-19 vaccines’ protection over time. We also in- vestigated the need for booster doses. In order to ensure solidity and reliability of the outcomes, this review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 2.1. Data sources We executed a comprehensive and systematic search in the online databases of PubMed, Scopus, Web of Science, and Cochrane on September 17th, 2021. Keywords were selected using the medical subject headings (MeSH) and previous studies. We provided the search terms for all the databases in Supplementary material 1. The search terms for PubMed were as follows: A. “COVID-19” OR “SARS-CoV-2” OR “SARS-CoV2” OR “2019- nCoV” OR “Novel Coronavirus” [Title/ Abstract] B. “Vaccine” OR “Vaccination” OR “Vaccinated” OR “Immu- nization” [Title/ Abstract] C. “Immunity duration” OR “Immunity period” OR “Protec- tion duration” OR “Duration”OR“Month” OR “Year”[Title/ Abstract] D. [A] AND [B] AND [C] 2.2. Study selection The retrieved records were imported to an EndNote file and the duplicates were removed. In a biphasic approach, three- independent researchers screened and selected eligible stud- ies. Inthe first phase, the retrieved records were reviewed and screened based on the relevancy of titles and abstracts. The full texts of the remaining articles were assessed based on el- igibility criteria in the second phase to select the most ap- propriate articles. Original articles discussing the efficacy of COVID-19 vaccines at least three months after full vaccina- tion (second dose in most cases, first dose in case of single- dose vaccines) were included in our study. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e53 Publications subject to one or more of the following exclu- sion criteria were excluded from our study: – Non-original studies, such as review articles – Case reports and case series – Abstract papers, conference abstracts, and other studies without available full texts – Ongoing clinical trials without yet published results – Preclinical studies and studies on subjectsother than hu- mans, such as pure laboratory or animal studies – Studies evaluating vaccine effectiveness in periods shorter than three months after becoming fully vaccinated against COVID-19. Three months was chosen as the cut-off point be- cause full vaccinations usually provide adequate protection in the first three months (13-15). 2.3. Data extraction Two researchers extracted the following information from the eligible studies included in the review (each recorded the data of half of the studies):first author (reference) ID, coun- try and year of study,type of study, study population, sex per- centage and mean age of the population, vaccine type, time passing from vaccination,changes in antibody levels, vaccine efficacy against infection, and disease severity parameters as well as mortality, authors’ opinion about booster dose, and summary of other notable findings. These data were trans- ferred into a word table, and then another independent re- searcher reviewed the extracted results to re-check and verify them. 2.4. Quality/risk of bias assessment We utilized the Newcastle-Ottawa Scale (NOS) risk assess- ment tool to evaluate bias risk of the included studies. This scale adds up to a total score of nine in three categories. These categories consist of selection, comparability, and ex- posure/outcome and receive maximum scores of four, two, and three, respectively (Table 2). 3. Results In this study, by applying systematic search strategies, 797 relevant records were identified and retrieved from PubMed, Scopus, Web of Science, and Cochrane. After a primary re- view of retrieved articles, 380 duplicates were removed, and the title and abstract of the remaining 417 articles were eval- uated. By applying the selection criteria, 388 articles were ex- cluded, and only 29 articles were screened by their full texts. After the review of full texts, 17 articles were excluded. Fi- nally, 12 articles met the inclusion criteria and were included in the final review (Figure 1). Table 1 summarizes the results of the studies. The studies were conducted in various countries with 15 countries in- volved overall; one study was multinational and included six countries (USA, Turkey, Germany, South Africa, Brazil, and Argentina), and the other studies were conducted in Belgium (n=2), USA, China, Estonia, France, Spain, Israel, Greece, Italy, and Kazakhstan (each n=1).The vaccine types in included studies were mRNA-based (n=10), and inactivated virus (n=2)vaccines. The interval between the administra- tion of the second dose of the vaccine and the antibody titer assessment varied between 4 weeks to 6 months. The major- ity of included studies observed acceptable antibody titers in most of the participants even after 6 months (16, 17); how- ever, the titers decreased in a considerable portion of the people(18). Due to the reduction in the antibody titer over time, several studies suggested administering the booster dose, especially for older patients and those with underlying conditions, such as patients with immunodeficiencies(17- 19).Table 2 demonstrates the results of the quality assess- ment. All the studies had acceptable quality assessment scores, but they mostly lacked adequate matching for con- founders. 4. Discussion COVID-19 pandemic is a serious global challenge due to its high prevalence and the emergence of new vari- ants.Vaccination is one of the best solutions to mitigate the immense burden of the virus, in addition to the social distancing, using face masks, and observing health proto- cols.We reviewed 12 articles concerning COVID-19 vaccina- tion, elicited antibody response, duration of triggered immu- nity, and the necessity of the booster dose. In 10 studies, the vaccine type was mRNA-based, and in two studies, it was in- activated vaccine. In seven studies, participants were health- care workers, adults, and individuals with cancer. The ma- jority of articles mainly discussed the importance of booster doses, since antibody titers decline over time. Favresse et al. reported that antibody titers significantly de- creased three months after vaccination with BNT162b2 in seronegative and seropositive healthcare workers (20).Con- sistently, the study by Erice et al. showed a reduction in anti-SARS-CoV-2 receptor-binding domain antibody (anti- RBD antibody) titers in healthy individuals three months af- ter the second dose; indicating that a booster dose could be beneficial(19).Terpos et al. also reported a decline in effec- tive antibody titers (anti-S-RBD antibody and neutralizing antibody) six months after vaccination(18). These findings emphasize the beneficial effects of a booster dose against COVID-19; particularly, in reducing the rate of hospitaliza- tion and mortality, which are specifically important in the el- derly and people with underlying diseases. A study by Gou et al. on efficacy of inactivated vaccines eval- uated 2 age groups, one of which mostly consisted of the el- derly. This study demonstrated the value of a booster dose, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem O. Dadras et al. 4 as there is always concern over elderly people’s morbidity and mortality (21),yet more studies are required in order to assess the antibody alteration in elderly population. In addition, a study by Waldhorn et al. showed a signifi- cant decrease in antibody titer over time. Since the study population was cancer patients with an average age of 66, it is possible that immunodeficiency and advanced age are both to blame for the considerable drop (22). However, more studies for assessment of antibody alterations in each group, separately, could be useful in determining the effect of each change in factor on antibody titer over time. In recent months,the COVID-19 wave attracted global atten- tion due to its new variant (Omicron B.1.1.529). Although this new variant has lower mortality, it is more contagious, spreads faster, and can even result in severe illness. This global issue could be best resolved by the enhancement of the immune system; therefore, the third dose of vaccine is beneficial to accentuate antibody response(23). Concerning the immune response, Hedges et al. found that vaccination causes higher levels of antibody in comparison with previous COVID-19 infection. This showed the neces- sity of vaccination even in individuals with previous COVID- 19 infection(24). Besides, it has been shown that a booster dose of the COVID-19 vaccine can elicit a strong antibody response that could protect the individuals from acquiring the disease and severe disease, and subsequently reduce the mortality and morbidity of the disease (11). Studies suggest that age plays an important role in vaccina- tion. The study of Naaber et al. reported that older peo- ple may have a weaker response to COVID-19 vaccines and also may have fewer side effects (16). Terpos et al. also showed that antibody titers decrease more slowly in younger persons; therefore, younger individuals had higher antibody titers compared to older people with the same number of days passing from vaccination (18). Likewise, Erice et al. ob- served that younger individuals (especially those aged 21 to 30) had higher antibody titers following COVID-19 vaccina- tion(19). Compared to other included studies, Zakaria et al. evaluated the younger study population (mean age: 28) and discovered that antibody titer decreased over time (25). Con- sidering this finding and based on the study by Terpos et al. (18), booster doses continue to play an important role. Terpos et al. also showed that underlying diseases such as diabetes or autoimmune diseases may affect the antibody titers, leading to lower neutralizing antibody titers(18). These findings showed that the efficacy of vaccines can be influ- enced by different factors, including age and underlying dis- ease. Therefore, a booster dose would be most beneficial in these vulnerable groups. However, it has been recently rec- ommended for all age groups from all backgrounds (11). 5. Limitations This study has several limitations. First, the number of included studies was limited and they did not encompass all types of vaccines, and the publications existed only on mRNA-based and inactivated vaccines. We also could not conduct a meta-analysis due to the limited number of stud- ies and their heterogeneity. Regarding the study populations, 7 out of 12 studies were performed on healthcare workers, an important group vulnerable to the COVID-19. This can be considered both a strength and a limitation, as health- care workers are a special and vulnerable group and re- quire specific attention, but this means that the number of population-based studies on the general population were limited. On the other hand, only one study targeted an- other important group, the immunocompromised patients, and further specific studies on this group are required. Fur- thermore, although the studies had acceptable quality as- sessment scores, many of them lacked adequate matching for confounders. A strength of the present review was that included studies were conducted in 15 countries, making the results more reliable worldwide. Overall, we could deduce the benefits of booster doses using the existing evidence. 6. Conclusion Studies have shown that the immunity due to COVID-19 vac- cines diminishes over time. Such decrease is more evident in older people and those with specific underlying diseases, such as immunodeficiencies. Furthermore, new COVID-19 variants, particularly Omicron, are on the rise and it has been documented that they may evade the immunity rendered by vaccines; therefore, immediate efforts are required to re- furbish the vaccines to trigger the appropriate antibody re- sponses against these new variants. Moreover, booster doses are recommended to enhance the overall immunity of the general population against COVID-19. 7. Declarations 7.1. Acknowledgments The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Research Center for HIV/AIDS, Tehran University of Medical Sciences, and Walailak University. 7.2. Availability of data and materials All data generated or analyzed during this study are included in this published article. 7.3. Authors’ contributions (1) The conception and design of the study:Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e53 (2) Acquisition of data: Amirali Karimi, Alireza Shojaei (3) Analysis and interpretation of data: Ava Amiri, Sara Mahdiabadi (4) Drafting the article: Amirata Fakhfouri, Armin Razi, Hengameh Mojdeganlou, Paniz Mojdeganlou, Alireza Barze- gary, Zahra Pashaei, Amir Masoud Afsahi, Parnian Shobeiri, Omid Dadras (5) Revising it critically for important intellectual con- tent: SeyedAhmad SeyedAlinaghi, Omid Dadras, Esmaeil Mehraeen (6) Final approval of the version to be submitted: all authors 7.4. Funding and supports This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 7.5. Competing interests The authors declare that there is no conflict of interest re- garding the publication of this manuscript. 7.6. Ethics approval and consent to participate Not applicable. 7.7. Consent to publication Not applicable. References 1. WHO Coronavirus (COVID-19) Dashboard [Available from: https://covid19.who.int/. 2. Mehraeen E, Oliaei S, SeyedAlinaghi S, Karimi A, Mirza- pour P, Afsahi AM, et al. COVID-19 in Pediatrics: A Sys- tematic Review of Current Knowledge and Practice. In- fect Disord Drug Targets. 2022; 22(5): e290921196908. 3. Mehraeen E, SeyedAlinaghi S, Karimi A. Can children of the Sputnik V vaccine recipients become symp- tomatic? Human vaccines & immunotherapeutics. 2021;17(10):3500-1. 4. Mehraeen E, Dadras O, Afsahi AM, Karimi A, Pour MM, Mirzapour P, et al. 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This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e53 Figure 1: PRISMA 2020 flow diagram for this systematic review. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem O. Dadras et al. 8 Table 1: Summary of findings based on each study First au- thor (ref- erence) Type of study Study popula- tion (N) Male (%) Mean age (SD) Type Time after vaccination Changes in antibody levels Vaccine efficacy against Author’s opin- ion about booster dose Summary of findings Infection Disease sever- ity Mort- ality A.Erice (19) Spain, 2021 Observa- tional study Adults 62% 46.0 years (SD 11.4 years) mRNA vaccine Serum samples were obtained a mean of 40.1 days (SD 2.8 days) and 88.8 days (SD 2.8 days) after the second dose of BNT162b2 Median [IQR] anti-RBD titres 1.5 months after vaccination were 9,356 [5,844 - 16,876] AU/mL; three months after vaccination, median anti-RBD titres had declined to 3,952 [2,190 - 8,561] AU/mL (p <0.001) Advanced severe COVID-19 has been reported in fully vaccinated individu- als a median of 39.5 days after the second dose of BNT162b2 A low anti-RBD antibody titer is one aspect related tothe advanced SARS-CoV-2 infection after complete vaccination with BNT162b2 J.Favresse (20) Bel- gium, 2021 Ongoing multi- center, prospec- tive, and in- terven- tional study Healthcare profes- sionals 22.5 43 mRNA COVID- 19 vaccine 3 months The maximal antibody response was reached between days 28 and 42 (2204 versus 1,863; P=0.20), with a 48.8–57.7-fold increase compared to day 14 (i.e. 38.2 U/mL) As calculated by the one-compartmental model, the estimated half-life of antibodies observed from data collected until 90 days after vaccination for seronegative members was 55 days (95% CI: 37–107 days) W.Gou (21) China, 2021 Clinical trial Healthy adults aged ≥18 41.1 and 59.5 in twoage groups The mean (standard deviation) age was 43.1 (9.6) years in participants aged 18–59 years and 66.7 (4.3) in those aged ≥60 years (79.2% aged 60–69 years) Inactivated 90 days Geometric mean titerof neutralizing antibody on day 90 after the third injection ranged from 87 to 129, respectively, among participants receiving three doses of vaccines The initial results of the Phase 1/2 trial among adults, including those aged 60 years or older, showed that the inactivated vaccine against SARS-CoV-2 was safe and immunogenic. J.F. Hedges (24) USA, 2021 Cohort 41.8 mRNA 6 months The neutralization titers had declined 6 months after vaccina- tion,similar to 6 months after natural infection. The antibody responses induced by vaccination were significantly higher than those induced by natural infection. Therefore, the study suggests that vaccination is still vital, even for those naturally infected or diagnosed with COVID-19. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2022; 10(1): e53 Table 1: Summary of findings based on each study First author (refer- ence) Type of study Study popula- tion (N) Male (%) Mean age (SD) Type Time after vac- cination Changes in antibody levels Vaccine efficacy against Author’s opinion about booster dose Summary of findings Infec- tion Disease sever- ity Mort- ality P.Naaber (16) Esto- nia, 2021 Longitudinal observa- tional Healthcare workers 42 42.5 mRNA 6 months In the first serum sample, the median anti-S-RBD IgG reached 540.0 AU/mL (IQR 64.5-1102.0). In the following tests, a progressive decay of antibodies was seen, up to the value of 55.7 AU/mL (IQR 26.2-84.7) at the 6-month follow-up This study may allow to define a protective antibody threshold, below which the risk of break-through infections significantly increases and which could, hence, guide the time point when to offer a booster dose. The study approves the persistence of anti-S-RBD neutralizing antibodies through 6 months after the vaccination. M.Pouquet (26) France, 2021 Longitudinal survey Health care workers RNA- based vac- cines 6 months E. Terpos (18) Prospective study Health care workers 32.9 48 mRNA 3 months Three months after the second vaccination (i.e., on D111), the decline in NAb titers was even more prominent with a median inhibition of 92.7% (SD 11.8) The longitudinal study is continuing in order to determine the time point of NAbs decrease below the positivity threshold, and the fading of protective immunity against COVID-19; when a booster vaccine dose might be necessary. Both NAbs and anti-S-RBD antibodies, the maximum levels are seen at day 36. A statistically significant decrease in both types of antibodies was observed after day36 up to day111 S. J. Thomas (9) 6 countries, USA, Turkey, Germany, South Africa, Brazil, Ar- gentina; 2021 Clinical trial Adolescents and adults 50.9 51 mRNA 6 months Vaccine efficacy of 91.1% BNT162b2 effectively prevents COVID-19 for up to 6 months after the second dose across various populations, despite the emergence of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem O. Dadras et al. 10 Table 1: Summary of findings based on each study First au- thor (ref- erence) Type of study Study popula- tion (N) Male (%) Mean age (SD) Type Time after vac- cination Changes in antibody levels Vaccine efficacy against Author’s opinion about booster dose Summary of findings Infec- tion Disease sever- ity Mort- ality SARS-CoV-2 variants, including the beta variant, and the vaccine continues to show a promising safety profile. M. Tré- Hardy(17) Belgium, 2021 Prospective study Health care workers 25.4 50.1 mRNA 5 months Antibody values went from 400 [400-400] AU/mL at 3 months after first injection to 221.0 [202.3-241.2] AU/mL at 6 months after first injection, and from 400 [400-400] AU/mL at to 400 [365.0-400] AU/mL at Introducing a booster dose, under certain circumstances, could have a significant impact in terms of public health All applicants still had detectable SARS-CoV-2 IgG antibodies up to 5 months after complete vaccination. I.Vicenti(27) Italy, 2021 Longitudinal study Health care workers (HCWs) 39.1 mRNA 3 months Previously infected vaccinated HCWs (n=23): 546 Uninfected vaccinated HCWs (n=13): 20 In uninfected HCWs completing the two-dose vaccine program, a third mRNA vaccine dose is a sensible option to counteract the substantial NtAb decline occurring at a significantly higher rate compared with previously infected, vaccinated HCWs Median NtAb at V2_90 (90±2 days after the second dose) was still significantly higher than median NtAb at V_0 (before receiving the first dose) both in HCWs with past mild disease (p=0.01) and in those ex- periencing asymp- tomatic infection (p=0.001). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2022; 10(1): e53 Table 1: Summary of findings based on each study First au- thor (ref- erence) Type of study Study popula- tion (N) Male (%) Mean age (SD) Type Time after vac- cination Changes in antibody levels Vaccine efficacy against Author’s opinion about booster dose Summary of findings Infec- tion Disease sever- ity Mort- ality I.Waldhorn(22) Israel, 2021 Prospective follow-up report of the primary study Cancer patients with solid tumors 55 66 mRNA 166 ± 29 days Both cohorts depicted a drastic decline in serology titer over time,but the titer remained above the threshold value There was no notable difference in the median absolute serology titer between the seropositive individuals within the two cohorts (patients vs. controls). K. Za- karia(25) Kaza- khstan, 2021 Clinical trial Adults aged 18 years and older 77.3 28 Inactiva- ted whole- virion 6 months An increase in the titers of neutralizing antibody was statistically significant, reaching Geometric Mean Titer of 5.1 (95% CI 3·5–7·6) on day 21 and Geometric Mean Titer of 100 (95% CI 77–129) on day 42. On day180 after the first immunization, the Geometric Mean Titer dropped to 7 (95% CI 5–7) In both trials, specific antibodies were detected in MNA and ELISA on study day 180, but the titers dropped in comparison today 42. SD: standard deviation; IQR: interquartile range; CI: confidence interval; S-RBD: spike protein receptor-binding domain; Ig: Immunoglobulin; NAb/NtAb: neutralizing antibody; MNA:microneutralization assay; ELISA:enzyme-linked immunosorbent assay. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem O. Dadras et al. 12 Table 2: The results of Newcastle-Ottawa scale (NOS) risk of bias assessment The first author (Reference) Selection (out of 4) Comparability (out of 2) Exposure/ Outcome (out of 3) Total score (out of 9) A.Erice(19) *** - ** 5 J.Favresse(20) *** * ** 6 W.Gou(21) *** - *** 6 J.F. Hedges(24) **** * ** 7 P.Naaber(16) **** * ** 7 M.Pouquet(26) *** * *** 7 E. Terpos(18) **** * * 6 S. J. Thomas(9) **** * ** 7 M. Tré-Hardy(17) *** * *** 7 I.Vicenti(27) **** * *** 8 I.Waldhorn(22) **** * *** 8 K. Zakaria(25) **** * ** 7 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References