key: cord-0852042-ak4c0yya authors: Noori, Maryam; Nejadghaderi, Seyed Aria; Arshi, Shahnam; Carson‐Chahhoud, Kristin; Ansarin, Khalil; Kolahi, Ali‐Asghar; Safiri, Saeid title: Potency of BNT162b2 and mRNA‐1273 vaccine‐induced neutralizing antibodies against severe acute respiratory syndrome‐CoV‐2 variants of concern: A systematic review of in vitro studies date: 2021-07-19 journal: Rev Med Virol DOI: 10.1002/rmv.2277 sha: 2a5457cd3022665b24a3975cacf6325a49f6ffeb doc_id: 852042 cord_uid: ak4c0yya BNT162b2 and mRNA‐1273 are two types of mRNA‐based vaccine platforms that have received emergency use authorization. The emergence of novel severe acute respiratory syndrome (SARS‐CoV‐2) variants has raised concerns of reduced sensitivity to neutralization by their elicited antibodies. We aimed to systematically review the most recent in vitro studies evaluating the effectiveness of BNT162b2 and mRNA‐1273 induced neutralizing antibodies against SARS‐CoV‐2 variants of concern. We searched PubMed, Scopus, and Web of Science in addition to bioRxiv and medRxiv with terms including ‘SARS‐CoV‐2’, ‘BNT162b2’, ‘mRNA‐1273’, and ‘neutralizing antibody’ up to June 29, 2021. A modified version of the Consolidated Standards of Reporting Trials (CONSORT) checklist was used for assessing included study quality. A total 36 in vitro studies meeting the eligibility criteria were included in this systematic review. B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) are four SARS‐CoV‐2 variants that have recently been identified as variants of concern. Included studies implemented different methods regarding pseudovirus or live virus neutralization assays for measuring neutralization titres against utilized viruses. After two dose vaccination by BNT162b2 or mRNA‐1273, the B.1.351 variant had the least sensitivity to neutralizing antibodies, while B.1.1.7 variant had the most sensitivity; that is, it was better neutralized relative to the comparator strain. P.1 and B.1.617.2 variants had an intermediate level of impaired naturalization activity of antibodies elicited by prior vaccination. Our review suggests that immune sera derived from vaccinated individuals might show reduced protection of individuals immunized with mRNA vaccines against more recent SARS‐CoV‐2 variants of concern. subunit completes membrane fusion. 4 Because the spike protein is an important mechanism of viral cell entry, it has been a potential target for vaccine development. 5 Due to the great numbers of viral genome replications that occur in infected individuals and the error-prone nature of RNA dependent RNA polymerase, 6 progressive accrual mutations do and will continue to occur. Despite ineffectiveness of most mutations to viral fitness, a few may provide beneficial features that could give the virus an opportunity to transmit more efficiently and evade host immune response. 7 As a result, efficient mutations could be the subject of natural selection and lead to emergence of novel SARS-CoV-2 variants that are able to expand rapidly across countries and overcome public health efforts to restrict the infection. However, as vaccines currently in circulation have been designed based on the spike sequence of the ancestral SARS-CoV-2 strain, outbreaks of novel variants could be a potential threat for compromising immunogenicity of these vaccines. [8] [9] [10] In recent months, several mutations have appeared in the spike protein, leading to identification of novel variants with several substitutions or deletions in the spike protein. The variants, which have potential to increase transmissibility, virulence, or evade available diagnostics, vaccines, and therapeutics, have been denoted as variants of concern. According to the World Health Organization were first emerged in the United Kingdom, South Africa, Brazil, and India, respectively, where they have rapidly become dominant and are currently spreading across the globe ( Figure S1 and S2). 11 Serum neutralization activity is a common predictor of protection against SARS-CoV-2 following natural infection or vaccination. 12, 13 Due to variations observed in the spike genome, effective protection from SARS-CoV-2 infection requires a sufficient breadth of neutralizing antibodies rather than potency alone. 14 Preliminary studies have shown that mutant viruses increase the affinity of binding to host cell receptors and diminish the susceptibility of neutralization by pre-existing antibodies raised through either prior infection or vaccination. [15] [16] [17] [18] In the present study, effectiveness of neutralizing antibodies elicited by two doses of mRNA based vaccine platforms, including BNT162b2 and mRNA-1273, was systematically evaluated according to variants of concern using data from in vitro studies. The guideline of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was followed for review reporting. 19 As the evaluation was on in vitro studies, the pre-specified protocol could not be published on the International Prospective Register of Systematic Reviews (PROSPERO). However, the protocol was pre-specified and no alterations to the proposed evaluation methods (including design and outcomes) occurred literature retrieval. Three online databases (PubMed, Scopus and Web of Science) and two preprint servers (bioRxiv and medRxiv) were screened for relevant records up to June 29, 2021. Search terms included 'SARS- Search results were exported to EndNote X8.0 (Clarivate Analytics, Philadelphia, PA, USA) reference manager software. Following removal of duplicates, titles and abstracts from remaining articles were screened against inclusion and exclusion criteria by two independent review authors. Studies requiring full-text review were again screened by two independent review authors, with discrepancies resolved through consensus, and where required a third author as arbiter. We contacted the corresponding authors for retrieving full-text of articles that we could not access to their fulltexts. Studies meeting the following criteria were included: (1) In vitro studies comparing 50% neutralization titre against SARS-CoV-2 variants of concern and a reference strain for samples obtained from vaccine recipients, (2) Studies reporting fold change of neutralization titre or displayed it in high resolution images, (3) Studies recruiting samples from individuals who received two doses of 30 μg BNT162b2 vaccine or 100 μg mRNA-1273 vaccine, (4) Studies utilizing viruses with at least one set of mutations as reported by WHO for each variant of concern, 20 and (5) Studies reporting the exact mutation in the spike protein of utilized viruses or reporting the strain name and Global Influenza Surveillance and Response System (GISAID; https://www.gisaid.org/hcov19-mutationdashboard/)-ID. Exclusion criteria were as follows: (1) Samples were collected from convalescent individuals who were not vaccinated, (2) The vaccine type was not clearly determined, (3) Recruited individuals received only one dose of vaccine, (4) Studies were conducted on samples from vaccinated mice or non-human primates, (5) Neutralization titre was measured for viruses with only a specific subset of mutations, and (6) Study types other than in vitro (e.g., clinical trials, animal studies, and systematic reviews). Two independent reviewers extracted the following characteristics from identified studies using standardized templates: first author's name, title, publication date, country of origin, sample size, gender and age of vaccine recipients, type of vaccine, history of previous SARS-CoV-2 infection, and days passed from the second vaccine dose that samples were obtained. Variant of concern type and its spike protein mutation profiles, type of reference virus, stain name or GISAID-ID for variants and reference viruses were also extracted. Where the mutation profile of spike protein was not reported, an additional source, that is the GISAID webpage were was searched. 21 Laboratory methods, including type of neutralization assay and source of the utilized viruses, fold changes in 50% neutralization titre, and relevant p-values were also recorded. If fold changes were not reported, neutralization titres were digitized from figures in papers with a digital extraction tool. 22 Disagreements between review authors were resolved by discussion and consensus, or where required consultation with a third reviewer. Given that no established guidelines currently exist for quality assessment of in vitro studies, two independent review authors used a modified version of the Consolidated Standards of Reporting Trials (CONSORT) tool, which was developed to appraise the quality of studies in dentistry. 23 Data analysis was performed using qualitative methodology with narrative synthesis. Included studies were categorized based on the variant of interest and type of vaccine. Tables summarizing outcome measures and related findings from each type of vaccine were made. Meta-analysis was not possible due to substantial differences across investigation methods, which was a pre-specified decision, therefore, no test for assessment of publication bias was performed. The systematic search identified 782 records of which 120 were duplicates and excluded. Following title and abstract screening of the remaining 662 records, 69 full text publications were screened for eligibility. Eighteen studies evaluated the effects of single mutations, [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] six studies evaluated the effects of other variants which were not variants of concern, 42-47 three were review NOORI ET AL. articles, [48] [49] [50] two studies were re-analysis of previously published articles, 51,52 two studies did not differentiate type of vaccines, 53, 54 two studies were conducted on animal subjects, 55,56 and one did not mention the exact mutations of viruses. 57 Finally, 36 publications met the inclusion criteria and were included in this systematic review ( Figure 1 ). 15, 16, 58, 59, [63] [64] [65] 69, 71, 74, 75 and both types of viruses were used as comparator strains in one study. 76 Fourteen studies utilized live virus neutralization assays, 15, 16, 58, 59, 61, 63, 64, 66, 68, 70, 72, 73, 75, 77 seven used pseudovirus neutralization assays, 60, 62, 65, 67, 69, 71, 74 and one used both types of assays. 76 Fifty percent neutralization titre was decreased as little a s2.6 fold or increased up to 3.8 fold in studies utilizing live virus neutralization assays, and decreased as little as 6.7 fold or increased up to 1.69 fold in studies utilizing pseudovirus neutralization assays, as compared with reference strain (Table 1) . Eight studies 18 Quality of included studies ranged from 4 to 9, using the modified version of the CONSORT checklist (Table S2 ). The average score was 7.8 points, reflecting 52% of the possible total score of 15. Potential sources of bias were primarily attributed to issues concerning sample size estimation and randomization methods, including sequence generation, allocation concealment mechanism, implementation, and blinding. In addition, a registered pre-specified protocol was not provided for any of the included studies. Furthermore, limitations were discussed in only half of the eligible studies. Figure 2 illustrates a summary of the modified CONSORT checklist per item. This systematic review found that the B. Mutations that occur in the RBD region of spike protein are of the greatest concern due to their potential to promote escape from the vaccine induced neutralizing antibody response, which predomi- In recent decades, several high throughput methods have been developed for quantification of neutralizing antibodies and the COVID-19 pandemic has provided a beneficial opportunity for expediting research on upgrading neutralization assays. 107 During the second and third wave of SARS-COV-2 infection in Qatar, The emergence of variants of concern highlights the beginning of viral antigenic drift, which may be going in a direction that eventually Our study relies on in vitro investigations, therefore, reduction in neutralization titres of antibodies against novel variants may not be generalizable to in vivo environments. In addition, the time period for collecting specimens following the second vaccination dose ranged from a few days to one month across studies, therefore, it is possible that antibody titres would have decreased over time to levels no longer able to provide adequate protection against mutant viruses. The recent emergence of multiple SARS-CoV-2 variants has disrupted confidence in the current generation of vaccines to provide adequate protection against COVID-19. Our review suggests that immune sera derived from vaccinated individuals might fail to protect people immunized by mRNA vaccines against more recent SARS-CoV-2 variants of concern; mutations present in B. EUA AT, Agnihothram S. 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