key: cord-0743193-n61nx9pg
authors: Lau, Oscar; Vadlamudi, Nirma Khatri
title: Immunogenicity and Safety of the COVID-19 Vaccines Compared With Control in Healthy Adults: A Qualitative and Systematic Review
date: 2021-10-15
journal: Value Health
DOI: 10.1016/j.jval.2021.09.003
sha: 7b14e80b87c1b8973145e403c119933a136c79f0
doc_id: 743193
cord_uid: n61nx9pg

OBJECTIVES: Emergence of severe acute respiratory syndrome coronavirus 2 infections and the resultant disease, COVID-19 led the world into 238 million cases and 4.8 million deaths over the first 22 months of the pandemic. While numerous vaccines have been developed to combat this pandemic, limited literature is available regarding the comparison of these vaccines. This study aims to systematically review and evaluate the immunogenicity and safety of COVID-19 vaccines compared with control arms in the healthy adult population. METHODS: A literature search was conducted in PubMed, MEDLINE, Embase, and Cochrane up to July 4, 2021. Randomized controlled trials assessing the immunogenicity of any dose of COVID-19 vaccine in adults by anti–severe acute respiratory syndrome coronavirus 2 immunoglobulin G antibodies geometric mean titers (GMTs) and neutralizing antibodies GMT response at 28 days postimmunization compared with the control groups in the healthy adults were considered for inclusion. Groups at day 28 with the highest GMT were further examined for their adverse events. RESULTS: Of the 341 citations retrieved, 19 were included. This covered a total of 16 vaccines involving 8342 subjects aged between 30.8 and 69.7 years, comprising 52.13% females. All studies reported GMT at or close to 28 days postvaccination compared with placebo and comparator, and 13 of 19 studies reported seroconversion rates. While 15 of 16 vaccines reported adverse events that ranged from mild to severe, 1 of 16 (AD26.COV2.S) noted 1 case of a vaccine-related serious adverse event—high fever 6 hours after vaccination. Local reactions (such as redness, pain, and swelling) and systematic reactions (such as fatigue, fever, and headache) were commonly noted. Safety between vaccines was similar; however, higher rates of severe adverse events were noted in Ad5-vectored COVID-19, AD26.COV2.S, ChAdOx nCoV-19, and mRNA-1273. No all-cause mortality was documented in any vaccines. CONCLUSIONS: All 16 vaccines elicited an immune response substantially higher than the control groups while maintaining tolerable safety profiles.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resultant disease, COVID-19, led the world into a pandemic with over 238 million cases and 4.8 million deaths, making it a global public health problem. Most exposed individuals experience mild infection, but those with chronic conditions and advanced age are at a higher risk of developing severe symptoms. 1, 2 Thus, Immunocompromised individuals are especially at higher risk of COVID-19-associated mortality than healthy populations. [3] [4] [5] Common symptoms experienced in mild cases are fever, cough, fatigue, shortness of breath, sore throat, and headache; severe complications include acute respiratory distress syndrome, kidney injury, and septic shock. 6, 7 COVID-19 is transmitted through respiratory droplets from an infected individual. Although symptomatic cases are the largest contributors to new infections, asymptomatic or presymptomatic carriers are also known to be potentially infectious. 8 Consequently, many countries implemented several approaches such as social distancing, widespread lockdown, and mandating the use of face masks to reduce the spread of COVID-19. 9,10 A review by Hossein-Khannazer et al 11 reported over 160 studies being conducted on antiviral drugs, immunotherapies, and monoclonal antibodies therapies used against COVID-19, though none were reported to be effective against COVID-19. With the lack of effective treatment, many have turned toward a preventative approach. As of October 2021, across several jurisdictions, there are 22 vaccines authorized for distribution against COVID-19 such as AZD1222 (ChAdOx nCoV- 19) , BBIBP-CorV, BNT162b2, CoronaVac, and mRNA-1273. 12 An additional 91 vaccine candidates are currently under development. For example, Novavax is presently under the phase III trial of a nanoparticle vaccine, NVX-CoV2373 (consisting of rSARS-CoV and M1 adjuvant). 12 In North America, both Pfizer (BNT162b2) and Moderna (mRNA-1273) have been

The quality of the studies included in this review was assessed according to the Cochrane risk of the bias assessment tool. 20 Using the risk-of-bias tool, participant blindness, reporting of data, participant outcome assessment, and randomization in the study period were evaluated. Study risks were characterized as low, some concerns, and high risk (see Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.09. 003). Accordingly, the risk of bias in each study was provided a quality score of good, fair, or bad (see Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021. 09.003).

General demographic information extracted includes the clinical trial registration identifier, country, funder or manufacturer, sex, mean or median age, number of dosages, study duration, study phases, and vaccine type. Study durations were estimated from the beginning of the recruitment date to the last vaccination date when not provided from the study.

The immunogenicity of a vaccine candidate was assessed by 3 factors. Both anti-SARS-CoV-2 spike protein and receptor-binding domain (RBD) subunits suggest the presence of immunoglobulin G (IgG) antibodies against COVID-19 antigens, reported in geometric mean titer (GMT), and are included as the same data item. 21 Neutralizing antibodies blocks viral activity in cell culture, often reported in the GMT, limiting 50% viral replication. 22 Seroconversion is indicated by the percentage of participants with statistically significant antibody levels between before and after treatment. 23 A highly immunogenic vaccine is indicated by a high humoral response (antispike IgG and neutralizing antibody) reported in GMT and having seroconversion in most or all participants. 23 COVID-19 vaccine immunogenicity data were reported at 28 days after the first dose. Studies reporting GMT in the median and interquartile range were converted to mean and 95% confidence interval (CI) using a conversion formula described elsewhere. 24 In this study, we evaluated the vaccine group with the highest average GMT in both antispike IgG and neutralizing antibody results at or closest to day 28, as investigators likely plan to include the best performing cohorts in the next clinical trial. Seroconversions details were included when available. The method of antibody measurement was documented as stated in the original study along with the assay information.

Moreover, any adverse events reported after the receipt of COVID-19 vaccine candidates experienced by the participants were evaluated as secondary outcomes. Adverse reaction rates were selected for reporting only in vaccine cohorts with the highest average GMT in both antispike IgG and neutralizing antibody results. Adverse events data were collected separately by first and second doses. If these data were not available separately for each dose, then adverse events data were recorded for both doses combined. Then, adverse reactions in COVID-19 vaccine candidates were compared with control groups. Fisher's exact test and chi-square test were performed using RStudio (R Core Team, Vienna, Austria).

In addition to the aforementioned data, we collected from studies that reported vaccine cohorts separately by age to compare immunogenic responses and adverse events between younger and older healthy adult populations.

The literature search strategy generated a combined 341 articles. Removal of 65 duplicates yielded 276 articles. Of those, 245 citations based on exclusion criteria during the title and abstract screening were removed. The remaining 31 articles were screened for full-text review. Of these, 12 were excluded based on the study design and intervention groups. Finally, 19 studies were found to be eligible for data collection and qualitative analysis (Fig. 1 ).

These 19 studies reported data on 16 vaccines (Ad5-vectored COVID-19, Ad26.COV2.S, BBIBP-CorV, BBV152, BNT162b1, BNT162b2, ChAdOx1 nCoV-19, CoronaVac, CoVLP, KCONVAC, KMS-1, mRNA-1273, rSARS-CoV-2, SCB-2019, WIV04 strain, and ZF2001) with 8342 subjects (52.13% females) and mean/median age ranging between 30.8 and 69.7 years old [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] (Table 1 ). In our study, 3222 randomized participants were included for safety and immunogenicity evaluation. A total of 9 studies were singlecountry multicentered trials, 25-27,31,35-37,39,41 9 were singlecentered, [28] [29] [30] [32] [33] [34] 38, 40, 42 and 1 study was done in 2 countries (Belgium and United States) across 12 sites. 43 All 19 studies were in phase I or II of clinical trials [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] ; additionally, Ramasamy et al 41 reported phase III trial data on ChAdOx nCoV-19. A total of 18 of 19 studies reported no vaccine-related serious adverse event. [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] Sadoff et al 43 reported 1 case of hospitalization after vaccination. No all-cause mortality was reported in any studies. [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] All 19 studies were found to be of good quality (Table 1) . Overall, 12 studies were considered low risk 25, [29] [30] [31] [32] [33] [34] [35] 38, 40, 42 and 7 studies were at risk for randomization process, 26 selection of the reported results, 30, 36, 37, 39, 41, 43 measurement of the outcome, 27 and deviation from the intended interventions (see Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j. jval.2021.09.003). 27 A total of 6 vaccines are inactivated SARS-CoV-2, 26,28-30,32,34,40 3 vaccines are lipid-nanoparticle encapsulated messenger RNA, 25, 27, 38, 39 1 is a plant-produced virus-like particle, 35 or more doses were given on separate days. The second dose was given at days 14, 26,29,30,32,34,40 21, 27,29,30,35,37-39,42 28, 25, 28, 29, 32, 34, 41 or 56 43 after initial injection. Clinical trials with 3 separate injections were WIV04 strain (day 0, 28, and 56) 30 and ZF2001 (day 0, 30, and 60). 31 Vaccines were compared with placebos (sterile saline, aluminum hydroxide), [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [37] [38] [39] [40] 42, 43 another vaccine (meningococcal vaccine MenACWY), 36, 41 or the experimental vaccine itself without accompanying adjuvant. 35 

The immunogenicity data are summarized in Figure 2 (including 95% CI when available). All 16 COVID-19 vaccines from 19 studies were determined to be immunogenic. [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] The recurring assessment date of immunogenicity across studies was day 28, 27, 29, 30, 32, 33, 36, 39, 41 with the exception of CoVLP, KCONVAC, rSARS-CoV-2, SCB-2019,WIV04, and ZF2001. 30, 31, 34, 35, 37, 42 Additionally, Walsh et al 27 developed a protocol for 2 separate vaccine candidates (BNT162b1 and BNT162b2), and therefore was assessed separately.

The highest immunogenic response cohorts from each citation are reported in Table 1 . [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] Overall, in these groups, antispike IgG antibody GMT ranged between 32.1 25, 36 and 342 989.1. 35 The neutralizing antibody GMT ranged between 19.2 31 Subsequently, an updated search was performed on July 4, 2021. 37 which was measured in IC greater than 99%.

As seen in Tables 2 and 3 , the rates of adverse events varied across studies based on dosage, vaccine type, and the vaccination [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] Of the 19 studies, 9 reported rates of local and systemic adverse events. 25, 28, [30] [31] [32] 37, 40, 43 Local adverse events ranged from 5.1% (dose 2) 28 to 100% (dose 2). 39 In the control arm, local adverse reactions ranged from 2% (dose 1) 28 to 30.43% (dose 1). 37 Similarly, systemic adverse events ranged between 1.2% (dose 2) 30 to 87.5% (dose 1). 38 Systemic adverse reactions ranged from 0% 30,32,40 to 39.13% (dose 2) 37 among individuals in the control arm. Generally, vaccine candidates were associated with significantly higher adverse events compared with the control arm (data not shown).

Severe adverse events after vaccination were reported in 12 studies. 25, 27, 31, 33, [35] [36] [37] [38] [39] [41] [42] [43] Commonly documented severe local adverse events were pain (0.67% 31 -8.33% 39 ) and tenderness (0.82% 36 -4.16% 37 ) ( Table 2) . Generally, severe systemic events (such as chills, fatigue, fever, and myalgia) were comparable between vaccine and control arm. The occurrence rate ranged between 1% (dose 2) 25 and 8.33% (dose 2), 27 0.4% (single dose) 33 and 11.1% (dose 2), 25 1.6% (dose 1) 41 and 12.5% (dose 2), 38 and 0.4% (single dose) 33 and 11.11% (dose 2), 25 respectively. Among participants in the control arms, severe cases were only identified in 2 studies 25, 29 and included fatigue (2.1%), 25 fever (3.57%), 29 and headache (1.1%). 25 A total of 4 vaccines (Ad5-vectored COVID-19, Ad26COV2.S, ChAdOx1 nCoV-19, and mRNA-1273) were associated with significantly higher adverse events compared with control arms 25, 33, 36, 43 (data not shown). These included events such as fatigue, chills, and malaise (Tables 2 and 3 ). 36 

Of the 19 studies, 6 presented immunogenicity data by age. 25 Neutralizing antibody of highest GMT group. [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] (C) Comparison of antispike IgG antibodies between age groups. 25, 27, 29, 38, 41, 42 (D) Comparison of neutralizing antibodies between age groups. 25, 27, 29, 38, 41, 42 The 95% CI was included if available. The vaccination date was adjusted to day 0 for all studies. Antispike IgG antibody was assessed on day 28 for all vaccines except Keech et al 37 43 reported antispike antibody with geometric mean concentration. Antispike antibody data were not reported for Pu et al, 40 Wu et al, 28 and Xia et al. 29 Antispike antibody control data were not reported for Pu et al 40 and Wu et al. 28 Ramasamy et al 41 antibody and neutralizing antibody GMT in younger adults compared with older adults (60 and older). Nevertheless, no statistical significance could be demonstrated in any studies (Fig. 2) . 25, 27, 29, 38, 41, 42 The 30 mg BNT162b1 and 20 mg BNT162b2 cohorts demonstrated the greatest difference in GMT in both antispike IgG antibody and neutralizing antibody. 27 The antispike IgG in 30 mg BNT162b1 for 18 to 55 years old was 23 516, compared with 6580 in 65 to 85 years old. 27 Similarly, 20 mg BNT162b2 was 12 464 for 18 to 55 years old, compared with 3056 for 65 to 85 years old. 27 The neutralizing antibody level in 30 mg BNT162b1 for 18 to 55 years old was 267, compared with 101 in 65 to 85 years old. 27 In contrast, the neutralizing antibody level in 20 mg BNT162b2 was 363 for 18 to 55 years old, compared with 84 in 65 to 85 years old. 27 Within the COVID-19 vaccine arms, younger and older adult adverse reaction rates were similar (Fig. 3) . For example, in local reactions, pain occurred in 37.50% 29 38 Similarly, systemic adverse reactions were more common in younger adults. Fatigue occurred between 0% 29 and 75.51% 41 in younger participants, compared with 0% 42 and 63% 25 in older adults. In younger adults, fever occurrences ranged between 0% 27 and 70.83%, 38 whereas in older adults it ranged between 0% 27 and 50.00%. 38 Finally, the incidence of headache was between 0% 29 and 65.31% 41 in younger participants, as compared with 4.17% 29 and 50.00% 27, 41 in older participants. Overall, adverse events were generally comparable between both age groups.

All 16 COVID-19 vaccine candidates were found to be safe, tolerable, and generate immunogenic responses against SARS-CoV-2. Out of 16 vaccines included in this study, 12 (Ad26.COV2.S, Ad5-vectored COVID-19, BBIBP-CorV, BBV152, BNT162b2, ChAdOx nCoV-19, CoronaVac, KCONVAC, KMS-1, mRNA-1273, WIV04 strain, and ZF2001) are now approved for distribution and public use across several nations, whereas 4 vaccines: BNT162b1, CoVLP, rSARS-CoV-2, and SCB-2019 are currently ongoing data collection. 12 The World Health Organization vaccine tracker consistently updates for new developments. 46 In our review, all COVID-19 vaccine candidates produced higher immunogenicity compared with their respective controls supported by antispike IgG, neutralizing antibody, and seroconversion data. These independent results complement one another to provide a better understanding of immune responses elicited by participants. Comparisons between antispike IgG and neutralizing antibody results have been previously examined. Brochot et al 21 noted that, although the antispike IgG GMT remained over time, neutralizing antibody titer plateaued or declined. This implied that SARS-CoV-2 may induce neutralizing antibody responses, but was not prolonged. As a consequence, Brochot et al 21 suggested that antispike IgG may be a better indicator of immunogenicity and should potentially be prioritized over neutralizing antibodies when appropriate.

The seroconversion reported by 13 of 19 studies provides evidence that their COVID-19 vaccine elicits an immune response. All participants in many experimental groups had seroconversion, but studies such as Zhang et al 32 (11 of 24, 45 .8%) and Zhu et al 33 (61 of 129, 47.28%) achieved less than 50% seroconversion of neutralizing antibodies (Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.09.003). 32, 33 There is evidence of reduced immunogenic response and increased variability in older adults, which may have affected the results in studies including adults over a certain age. 47, 48 Additionally, Zhu et al 33 discussed that participants with preexisting exposure to viral vaccine vectors could hinder the immune responses induced by similar vaccines in the future. 33, 49 Thus, more than 1 dose may be required for adequate immunity against COVID-19. 33 Finally, a recent correspondence by Normark et al 50 suggested that a heterologous boost of mRNA-1273 after the initial vaccination of ChAdOx1 nCoV-19 was found to be able to neutralize the B.1.351 variant and provide greater immunogenic response than a homologous boost vaccination. Thus, the heterologous boost of different vaccine types could be of interest. In summary, various factors such as age and type of vaccines can affect the immunogenicity of COVID-19 vaccine candidates.

Antibody measurements can often be unstandardized in research laboratories. Folegatti et al 36 indicated that producing data on neutralizing antibodies requires demanding work and that the laboratory must also determine the IC to quantify viral activity. This can lead to unstandardized reporting between vaccine studies, particularly demonstrated in the rSARS-CoV-2 vaccine by Keech et al 37 using microneutralization assay IC greater than 99% (compared with Mulligan et al 39 or Ramasamy et al, 41 which used plaque reduction neutralization test IC of 50% and microneutralization assay IC of 80%, respectively). The high variance between laboratory standards, measurement dates, and evaluation points leads to discordant results. 51 Thus, the GMT between studies can only qualitatively indicate immunogenicity. A standardized procedure between all studies would be ideal, but implementation proves to be difficult because of the high variability of the measurement procedures. 51 Salje et al 51 recommended a plaque reduction neutralization test of 75% as an optimum evaluation point for its lower variance.

From the 19 studies included, adverse events were found to be tolerable in all 16 vaccines. Participants experienced adverse events such as pain, fatigue, and fever. One case of vaccine candidate-related serious adverse event was noted in the Ad.26COV2.S. Nevertheless, because this was the only occurrence, the safety of the Ad.26COV2.S. is deemed to be acceptable. 43 In alleviating overall adverse events caused by COVID-19 vaccines, paracetamol was noted to be effective. 27, 36 Thus, all COVID-19 vaccine candidates are considered tolerable and medication is suggested in events such as fever.

Adverse reaction rates in control and vaccine arms varied across all studies. This is potentially attributed to both sample size and control arms. Folegatti et al 36 included 487 randomized participants, whereas Mulligan et al 39 included 12. Subtle differences may require a larger sample size to detect, which may not be identified given the varying sample sizes. 52 In addition, control arms were different between studies, which consists of saline, another vaccine such as MenACWY, or a vaccine with or without adjuvant. 35, 36, 41, 53, 54 Thus, the comparison of adverse events between studies was limited by the differences in sample sizes and controls used. Regardless, we found that the adverse reaction rates of COVID-19 vaccines are generally comparable with placebo.

In this study, we found comparable immune responses against COVID-19 vaccines between age groups. Immunogenicity profiles of BNT162b1 and BNT 162b2 from Walsh et al 27 noted a considerably higher GMT average in both the antispike IgG and neutralizing antibodies in the 18 to 55 years age group compared with the 65 to 85 years group. Nevertheless, none of the vaccines were statistically suggestive of age correlation with immunogenicity. 29, 41 Additional studies are needed to investigate if immune responses to COVID-19 vaccines differ by age. --------------------------------------------------------------- Figure 3 . Safety and tolerability comparison of COVID-19 vaccines by age. 25, 27, 29, 38, 41, 42 27 (G) Comparison of the BBIBP-CorV vaccine between age groups of 18 to 59 and 60 years or older. 29 All adverse reactions were reported after the second dose by study participants. yrs indicates years.

Similarly, both local and systemic adverse reactions occurred more commonly in younger adults. Of note, statistical significance was not clearly indicated for the adverse reactions by age groups, as discussed previously. In all studies reporting by age cohorts, younger adults experienced higher incidences of pain, redness, and swelling compared with older age groups. 27, 29, 41 Similarly, common systemic adverse reactions, such as fever, were reported more often in younger adults than older adults. The overall trend in all adverse reactions provides evidence that younger adults are more likely to experience adverse reactions compared with older adults.

This study has multiple drawbacks. First, we did not conduct meta-analysis as different vaccine candidates were included along with huge population variances, variation among assays, dosage amounts, number of doses, and time between doses. Instead, we determined that a qualitative review would highlight current knowledge gaps. Second, COVID-19 vaccine research is an urgent global subject; this makes standardization in data collection and reporting difficult. For instance, data presentation varied between studies, immunogenicity data were not consistently collected on day 28 for multiple studies, and thus, could not allow for metaanalysis. 30, 31, 34, 35, 37 Additionally, this systematic review also limits the generalizability of results only to the healthy adult populations. Whereas the populations most at risk for severe illness after SARS-CoV-2 infections are the elderly and those with comorbid conditions, none of the studies included comorbid participants, and although older adults were studied, sparse data make it difficult to assess if certain vaccines work equally well in older adults. Massarweh et al 55 indicated that there is evidence of immunogenic response toward messenger RNA vaccines in individuals with cancer; thus, immunocompromised individuals could be considered for future vaccination studies.

Our study results are generally consistent with previous systematic reviews by Yuan et al, 15 Pormohammad et al, 16 and Kai et al. 17 All systematic reviews found that all vaccines were generally tolerable. Trends such as increased immunogenicity after booster dose were also consistently noted. 17 Comparing between systematic reviews, Pormohammad et al 16 and Kai et al 17 studied safety and efficacy, whereas Yuan et al 15 and our study examined safety and immunogenicity. To our knowledge, this systematic review is the most up-to-date safety and immunogenicity review, with greater sample size and number of studies (14 more studies) compared with Yuan et al. 15, [25] [26] [27] [28] [29] 31, 36, 38, [40] [41] [42] [43] COVID-19 vaccine systematic reviews are not without limitations. To begin, Yuan et al 15 did not address the complex relationship between study vaccines and the method of immunogenicity data collection. As we previously discussed, the standardization of neutralizing antibody measurement is not well defined, and thus, laboratory differences may hinder the accuracy of pooled immunogenicity data. 51 This was briefly mentioned by Kai et al. 17 In the study by Pormohammad et al, 16 vaccine studies were pooled into vaccine types for meta-analysis; this makes the comparison of safety and efficacy only applicable between different types of vaccines rather than individual manufacturers. Furthermore, none of the studies were able to address concerns regarding COVID-19 vaccines and age, or rare adverse events such as vaccine-induced immune thrombotic thrombocytopenia and myocarditis. [15] [16] [17] 56, 57 Finally, this systematic review highlights the strengths and limitations of ongoing COVID-19 vaccine research. In addition to producing safe, tolerable, and immunogenic vaccines, investigators must make an attempt to standardize reporting of all clinical trial data to facilitate appropriate comparison with other vaccine candidates. Further data on long-term effectiveness and a follow-up in all studies for participants at 6 months, 1 year, and 5 years after vaccination are needed.

All 16 vaccines in this review exhibited a substantial increase in immune response compared with control arms. Subjects in COVID-19 vaccine arms experienced an overall higher rate of adverse events compared with control arms. Ad5-vectored COVID-19, AD26.COV2.S, ChAdOx nCoV-19, and mRNA-1273 were associated with increased severe adverse reactions. One case of serious adverse event was noted in Ad26.COV2.S. Additional studies are needed to report on the long-term effects of these vaccines.

Supplementary data associated with this article can be found in the online version at https://doi.org/10.1016/j.jval.2021.09.003.

and Author Information Accepted for Publication

Correspondence: Nirma Khatri Vadlamudi, MPH, BS, BA, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: nirma. vadlamudi@ubc.ca Author Contributions: Concept and design: Lau, Vadlamudi Acquisition of data: Lau, Vadlamudi Analysis and interpretation of data: Lau, Vadlamudi Drafting of the manuscript: Lau and Vadlamudi Critical revision of the paper for important intellectual content: Lau and Vadlamudi Statistical analysis: Lau, Vadlamudi Provision of study material or patients: Vadlamudi Administrative

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Funding/Support: The authors received no financial support for this research.