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COVID-19 AŞILARI META-ANALİZ

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İNDİRMEK İÇİN BURAYA TIKLAYIN

ÖZET

 

Bu çalışma sistematik olarak clinik çalışma aşamasındaki aşıların etkinlik, immünojenite ve yan etkilerini değerlendirebilmek için özetlenmiş ve analiz edilmiştir.12 mart 2021 tarihine kadar olan konu ile ilgili bütün yayınlar ve veritabanları toplanmış ve araştırılmıştır. Toplam 25 çalışmadan(123 veritabanı) ,Covid-19 aşısı olmuş 58,889 kişi ve 46,638 plasebo almış kişi meta-analiz çalışmasına dahil edilmiştir. Toplamda faz 2 ve faz 3 çalışmalarında mRNA bazlı aşılar %94,6(95%cı 0,936-0,954) ve adenoviral vektör aşıları %80,2 (95%cı 056-0,93) etkinlik göstermişlerdir. Adenoviral vektör aşılarının reseptör bağlayıcı protein antijenine karşı etkinliği birinci dozda %97,6 (%95 CI 0,939-0,997) ve ikinci dozdan 3 hafta sonra %98,2 (%95 CI 0,980-0,984) olmak üzere en yüksel bulunan aşı idi. Diyare ve artralji haricindeki yan etkiler eçısından mRNA bazlı aşılar en yüksek orana sahip bulundu. Enjeksiyon bölgesindeki kızarıklık hariç olmak üzere adjuvanlı ve adjuvansız aşılar arasında aliminyum adjuvanlı aşıların en düşük yan etki potansiyeline sahip olduğu görüldü. Birinci dozdan sonra en etkili aşı sırasıyla adenoviral vektör aşıları ve mRNA bazlı aşılar olarak değerlendirildi. mRNA bazlı aşıların daha yüksek yan etki insidansına sahip oldukları görüldü. Genel olarak az sayıda cidi yan etki ve yüksek düzeyde etkinlik olduğu görüldü.

 

TARTIŞMA

 

Aşıların amacı insanları enfeksiyon ve bulaştan korumaktır. Her ne kadar medya ya da siyasetçiler bazı ciddi iddialarda bulunsa da acil kullanım onayı almış aşılar açısından henüz etkinlik ve yan etki anlamında yeteri kadar tecrübemiz yok. Bu nedenle bu meta-analiz çalışmasında bizler mevcut aşıların etkinlik ve yan etki potansiyellerini değerlendirmeye çalıştık. Bu çalışmada her bir aşı gruu için genel ve hedef spesifik antijene karşı olan etkinliği değerlendirdik. Çalışmamızda aşıların birinci doz ve ikinci doz sonrası etkinliklerinin anlamlı ölçüde değiştiğini gördük. Bu nedenle ikinci dozun uygulanmasının etkinlik açısından son derece önemli olduğunu belirtmek isteriz. Totalde mRNA aşılarının etkinliği %94,6 olarak değerlendirilmiştir. mRNA bazlıu aşılar 1. Dozdan 1 ay sonra %70, 2. Dozdan 1 ay sonra ise %99,5 nötralizan antikor geliştirmiştir. Ne yazık ki elimizde mRNA aşılarının birinci dozdan sonra geliştirdikleri RBD protein antikoruna ait bir data bulunmamaktadır. mRNA aşılarının ingiltere(B1,1,7 -20I/50y.v1) varyantına karşı etkili olduğu, ancak güney afrika(B1,351- 20H/501Y.V2) mutantına karşı daha az etkili olduğu görülmüştür. 2. Dozdan 1 hafta sonra wuhan virüsü ile karşılaştırıldığında B1,351 varyantına karşı oluşan antikor titresinin daha düşük olduğu görülmüştür. B1,351 varyantı s-protein içerisinde iki varklı substant taşımaktadır ve bu durum 3 farklı terapötik olarak ilişkili antikordan kaçmasını sağlamaktadır. Bu durum reinfeksiyonun önünü açabilecek ve spike protein bazlı aşıların etkinliğini bir miktar azaltabilecek bir etken gibi görülmektedir. Adenoviral aşıların total etkinliği bu çalışma soncuda %80.2 olarak bulunmuştur. Tek bir doz sonrası en yüksek etkinlik adenoviral vektör aşılarında tespit edilmiş olup bu Anti-RBD antikorlar plasebo ile karşılaştırıldığında ilk dozdan sonraki 3. Haftada %96,7, 4. Haftada ise %96,6 olarak tespit edilmiştir. Johnson&johnson gibi bazı adenoviral aşıların muhtemel bir nedenden dolayı tek dozda etkili düzeyde anti RBD antikor geliştirebileceği düşünülmektedir. Ancak şu ana kadar adenoviral vektör aşılarının 4 haftadan uzun etkilerini ortaya koyan bir çalışma yayınlanmamıştır. Diğer aşılar için de henüz total etkinlik yayınlanmamış olup daha çok antijen spesifik etkinlikler değerlendirilmiştir. Pro-subunit aşısı 1. Ayda en yüksek anti-spike etkinlik gösteren aşı olmuştur. VLP aşılarının etkinliği diğerlerine göre daha düşük bulunmuş olup anti-RBD etkinlik 1. Doz sonrası %23,8, ikinci doz sonrası ise %78,7 olarak değerlendirilmiştir. VLP aşılarına ait bütün raporlar faz I aşamasına ait olup bu durum aşıların düşük etkinliğine bağlı olabilir. Herhangi bir aşının immün yanıt aktivasyonu ya da enjeksiyon bölgesi doku travması sonrası ciddi bir yan etkiye neden olması beklenmemektedir.Bu çalışmalarada aşı ve plasebo grupları değerlendirildiğinde RNA bazlı aşıların reaktojenite açısından daha fazla yan etki gösterdiği ve bu yan etkilerin bölgesel ağrı, ateş, kızarıklık, halsizlik, kas ağrısı, baş ağrısı, endurasyon kusma ve kaşıntı gibi yan etkiler olduğu görülmüştür. Bu aşılarda öksürük gibi bir yan etki görülmemiş, diyare ve artralji gibi yan etkiler ise daha az görülmüştür. Negatif anlamdaki taraf tutmadan da kaçınarak söylememiz gerekir ki bu durum daha ciddi bir immün yanıta neden olan RNA aşılarının daha yüksek etkinliğe sahip olabileceğinin ciddi bir kanıtı olabilir. İlave olarak bu aşının anafilaksi ya da allerjik reaksiyon gibi ciddi bir yan etkiye sebep olmadığını da söylemek gerekir. Açlışmalarda hem placebo hem de aşı grubunda sadece birer adet anafilaksi görülmüştür. Yan etkiler konusunda adenoviral aşılar diğer aşılar ile kıyaslandığında daha çok diyare ve artraljiye sebep olmuşlardır. Yakın zamanda Yuan ve arkadaşları tarafından gerçekleştirilen bir meta-analitik derlemede aşının anlamlı düzeyde bir sistemik yan etki göstermediği, sadece ağrı, bölgersel kaşıntı ve kızarıklık gibi enjeksiyon yerine ait yan etkiler ile ilişkili olduğu görülmüştür. Bu aşıda da sadece 1 adet anafilaktik şok görülmüştür. Astra azeneca aşısında muhtemelen yaygın ileri yaş kullanımına da bağlı olduğu düşünülen az sayıda ciddi derin ven trombozu ve pulmoner emboli vakası görülmüştür. Ancak elimizdeki data sebep sonuç ilişkilerini düzgün kurmak açısından yetersizdir. Benzer olarak Johnson&Johnson aşısı için de Nisan 2021 de FDA tarafından nadir bir kan hastalığı problemi olan trombositopenik tromboz neticesinde cerebral venöz sinüs trombozuna neden olmasından şüphelenildi. Aynı zamanda mRNA bazlı bir aşı sonrası da bir derin ven trombozu (DVT) vakası rapor edildi. mRna ve adenoviral aşılar için ciddi bir yan etki olan anafilaksi de nadir olarak rapor edildi. Toplamda devam eden aşılama programları içerisinde hayatı tehdit eden yan etkiler son derce nadir görüldü. Elimizdeki data aşının tetiklediği immün trombotik trombositopeni(VITT) açısından dikkatli olmamız gerektiğini söylüyor. VITT; trombositopeninin eşlik ettiği tromboembolik olaylar ile karakterize, serebral ya da abdominal arteriyel pıhtılaşma, ciltte kolay morarma, kanamalı yeni ve/veya şiddetli baş ağrısı, karın ağrısı, ekstremitede soğukluk veya his kaybı gibi bulguların aşıdan 4 ila 28 gün sonra ortaya çıkması durumudur. Bu durum beyindeki venöz sinüs, büyük damarlar, vücudun diğer bölgesindeki damarlar(karın, kollar, bacaklar ) düşük trombosit sayısı ile beraber tromboze olmasının sonucudur. Bu olaylar nadir olmakla beraber bugüne kadar Pfizer/Biontech, Moderna, Johnson&johnson ve adenoviral vektör aşıları için kaydedilmiş vakalardır. Elimizdeki veriler VITT analizi yapmak için yeterli değildir. VLP subunitli aşılar ve inanktif virüs aşılarında adjuvanlar kullanılmaktadır. Adjvanlar IgG1 ve nötralizan antikjor titrelerini artırmakta önemli bir role sahiptir. Aynı zamanda aşılar üzerinde koruyucu etkisi de vardır. Aliminyum tuzları, emulsiyonlar ve tlr antagonistleri gibi bir sürü farklı adjuvan Covid aşıları için kullanılmaktadır. Adjuvanlı Covid-19 aşılarının yan etkileri üzerine yapılan çalışmalar en düşük yan etki profilinin aliminyum adjuvanlı aşılarda olduğuna işaret ediyor. Alüminyum adjuvanlı aşılar daha çok enjeksiyon bölgeinde şişlik ve kaşıntıya neden olurken adjuvansız aşılar yorgunluk, kusma, diyare, kızarıklık, kas ağrısı ve ateş gibi imünopatolojik yan etkilere sebep oluyorlar. Sonuç olarak bu çalışmadaki data adjuvanlı ya da adjuvansız aşılar içerisinde en düşük yan etki potansiyelinin alüminyum adjuvanlı aşılarda olduğunu gösteriyor. Çalışmanın kısıstlılıkları; 1)bazı aşılar için birinci doz ve ikinci doz için etkinlik yada antijen spesifik yanıt değerlendirilmemiştir. 2)bazı çalışmalarda gerek vaka sayısı ve gerekse de yeteri kadar coğrafi ekonomik ve yaş dağılımına dikkat edilmeden yapıldığından taraf tutma olabileceği değerlendirilebilir 3) aşılama zamanı ile covid-19 pandemisinin gerçekleri birarda değerlendirildiğinde daha doğru sonuçlar verecektir. 4) farklı aşılar sonrası IgG ve IgM düzeyleri birinci ve ikinci doz sonrası ciddi varyasyon gösterdiğinden bu meta-analize dahil edilmemiştir.5)hamileler ve farklı yaşam şeekline sahip hastaların değerlendirilmesi için yeterli data yoktur. 6) bütün çalışmalar aşının birinci y da ikinci dozundan yaklaşık bir ay sonra yapıldığı için uzun dönem etkileri değerlendirmek için elimizdeki data yetersizdir. 7)veritabanlarını değerlendirirken taraf tutmadan kaçınmak için ilişkili bütün yayınları toplayıp Egger’s regresyon analizini uyguladık. Bu testin sonucunda taraf tutmaya ilişkin anlamlı veriye rastlamadık. Ancak yine de sonuçları değerledirirken güvvenilirlik açısından yukarıda da açıkladığımız kısıtlılıkları gözönünde bulundurmanız faydalı olacaktır.

 

ORJİNAL MAKALE

 

Review Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials Ali Pormohammad 1 , Mohammad Zarei 2 , Saied Ghorbani 3 , Mehdi Mohammadi 1 , Mohammad Hossein Razizadeh 3 , Diana L. Turner 4 and Raymond J. Turner 1,* Citation: Pormohammad, A.; Zarei, M.; Ghorbani, S.; Mohammadi, M.; Razizadeh, M.H.; Turner, D.L.; Turner, R.J. Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines 2021, 9, 467. https://doi.org/10.3390/ vaccines9050467 Academic Editors: Soo-Hong Lee, Hansoo Park, Jagathesh Chandra Rajendran and K.S. Jaganathan Received: 5 April 2021 Accepted: 28 April 2021 Published: 6 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; ali.pormohammad@ucalgary.ca (A.P.); mehdi.mohammadiashan@ucalgary.ca (M.M.) 2 John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; mzarei@hsph.harvard.edu 3 Department of Virology, Faculty of Medicine, Iran University of Medical Science, Tehran 1449614535, Iran; vet.s.ghorbani@gmail.com (S.G.); razizadeh.mh@iums.ac.ir (M.H.R.) 4 Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; dturner23@me.com * Correspondence: turnerr@ucalgary.ca; Tel.: +1-(403)-220-4308 Abstract: The current study systematically reviewed, summarized and meta-analyzed the clinical features of the vaccines in clinical trials to provide a better estimate of their efficacy, side effects and immunogenicity. All relevant publications were systematically searched and collected from major databases up to 12 March 2021. A total of 25 RCTs (123 datasets), 58,889 cases that received the COVID-19 vaccine and 46,638 controls who received placebo were included in the meta-analysis. In total, mRNA-based and adenovirus-vectored COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) and 80.2% (95% CI 0.56–0.93) efficacy in phase II/III RCTs, respectively. Efficacy of the adenovirusvectored vaccine after the first (97.6%; 95% CI 0.939–0.997) and second (98.2%; 95% CI 0.980–0.984) doses was the highest against receptor-binding domain (RBD) antigen after 3 weeks of injections. The mRNA-based vaccines had the highest level of side effects reported except for diarrhea and arthralgia. Aluminum-adjuvanted vaccines had the lowest systemic and local side effects between vaccines’ adjuvant or without adjuvant, except for injection site redness. The adenovirus-vectored and mRNA-based vaccines for COVID-19 showed the highest efficacy after first and second doses, respectively. The mRNA-based vaccines had higher side effects. Remarkably few experienced extreme adverse effects and all stimulated robust immune responses. Keywords: COVID-19; SARS-CoV-2; vaccines; efficacy; side effect; randomized clinical trial; meta-analysis 1. Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a non-segmented positive-sense, single-stranded ribonucleic acid (RNA) beta coronavirus [1] that was first reported in Wuhan, China. The SARS-CoV-2 infection causes the coronavirus disease 2019 (COVID-19) that became a global pandemic and public health crisis. Over 140 million infected and 3 million deaths are reported from COVID-19 by April 2021, with the death rate accelerating; according to WHO, the case fatality ratio (CFR) of SARS-CoV-2 ranges from less than 0.1% to over 25% depending on the country [2]. To overcome this pandemic, vaccination is the hope for a safe and effective way to help build protection and reduce disease spread [3]. More than 200 COVID-19 vaccine candidates presented in different stages of development and over 50 candidates have reached clinical trials to date [4], including: Oxford-AstraZeneca’s ChAdOx1/AZD1222, Moderna’s mRNA-1273, Pfizer-BioNTech’s mRNA BNT162b2, Gamaleya’s Sputnik V, Johnson & Johnson’s INJ-7843735/Ad26.COV2.s, CoronaVac, Sinopharm’s BBIBP-CorV, Novavax’s NVX-CoV2373, EpiVacCorona, CanSino’s Convidicea (Ad5-nCoV), SinoVac’s Vaccines 2021, 9, 467. https://doi.org/10.3390/vaccines9050467 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, 467 2 of 21 CoronaVac, Anhui Zhifei Longcom’s ZF2001, GlaxoSmithKline and Medicago’s CoVLP, and Bharat Biotech’s BBV152/Covaxin. Different strategies have been considered for the development of vaccines against SARS-CoV-2 based on the following vaccine platforms: (I) Nucleic acid mRNA-based vaccines are the newest generation of vaccine production approach [5]. The mRNA vaccine technology is a single-stranded RNA molecule that carries a portion of the coding sequence for the peptide or protein from the virus that can be synthesized in the cytoplasm (ribosomes). The resulting antigen triggers an immune response, including the production of antibodies [5]. For instance, the current vaccines developed by the companies Pfizer and Moderna utilize synthetic mRNA encoding the sequence of the coronavirus’s signature spike protein (S-protein) that is then encapsulated within a lipid vesicle nanoparticle. (II) Viral vector vaccines that are developed with new biotechnology [6]. A modified existing virus, able to infect human cells, is introduced carrying the genetic code of the target virus antigen in order to stimulate an immune response. Oxford-AstraZeneca, Gamaleya, CanSio and Johnson & Johnson developed their vaccines based on a DNA sequence encoding the S-protein inserted into the genome of a modified safe adenovirus. (III) Whole-Pathogen Inactivated virus vaccines consisting of killed/inactivated whole viruses or virus fragments. Here the pathogen’s genetic material is destroyed by heat, chemicals, or radiation, so that they cannot replicate but their presence can still stimulate immunogenicity [7]. Sinopharm, SinoVac, and Bharat Biotech’s vaccines were produced by inactivating the SARS-CoV-2 with B-propiolactone, but all the viral protein remains intact. (IV) Subunit vaccines that contain a fragment of the pathogen, either a protein (Pro-subunit), a polysaccharide, or a combination of both, without introducing viable pathogen particles [8]. Lack of genetic material makes them safe and non-infectious/non-viable. Novavax and Anhui Zhifei Longcom applied this technology for the development of their vaccine, using nanoparticles coated with synthetic S-protein and an adjuvant for boosting the immune response. Virus-like particle (VLP) vaccines, also a subunit vaccine, mimic the native virus structure, but contain no viral genetic material [9]. A VLP presents the antigen inserted on a nanoparticle surface. GlaxoSmithKline and Medicago used a plant-derived platform to produce a particle that elicits neutralizing antibody and immune cell (e.g., TH1 T cell) responses against COVID-19. The structural proteins of SARS-CoV-2 include four major proteins: spike (S), membrane (M), and envelope (E) part of the viral surface envelope, and the nucleocapsid (N) protein in the ribonucleoprotien core. Among viral surface elements, the S-protein is a primary target for vaccines and therapeutic development against COVID-19 due to its role in the receptor recognition for cell entry and cell membrane fusion process. The trimeric S-protein contains two subunits, S1 and S2. The S1 contains a receptor-binding domain (RBD), which is responsible for recognizing and binding to the host receptor angiotensinconverting enzyme 2 (ACE2), while the S2mediates the membrane fusion process by forming a six-helical bundle (6-HB) via the two-heptad repeat (HR) regions [10]. However, S1 is the immunodominant antigen during CoV infections and induces long-lasting and broad-spectrum neutralizing antibodies (NAbs) and T-cell immune responses against the RBD. Thus, the S-protein and the RBD serve as the promising targets of SARS-CoV-2 vaccines and the predominant antigenic target for developing a vaccine [11]. Other antigenic targets, such as non-structural proteins (nsp) 3, nsp8-10 [12], papain-like proteases (PLpro), and cysteine-like protease (3CLpro) [13] can be considered an alternative for vaccine development, but these are expected to elicit less of an immune response. Efficacy and safety, thus side effect profiles, are core vaccine competencies required by medical care systems and public health. To the best of our knowledge, there is still no comprehensive comparative study around the efficacy and safety of COVID-19-related vaccines. In this regard, we provide here a meta-analysis on available randomized clinical trial (RCT) publications providing information on the efficacy and side effects of COVID-19 vaccines. Vaccines 2021, 9, 467 3 of 21 2. Methods 2.1. Search Strategy The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) recommendations were followed in this analysis [14]. We searched all clinical trial publications related to SARS-CoV-2 vaccines from the following databases: Scopus, EMBASE, Medline (via PubMed), and Web of Science. All studies published up to 12 March 2021 were searched without language restriction by three independent reviewers. Search medical subject headings (MeSH) terms used were “Covid-19 Vaccine”, “SARS-CoV-2 Vaccine”, “clinical trial” or “phase trial”, and “randomized”, as well as all synonyms. We used the Center for Disease Control (CDC), World Health Organization (WHO), and Google Scholar databases/academic search engines to look for unpublished and grey literature. References and citation lists of selected articles and reviews were also reviewed for any other relevant literature (forward and backward citation, recommended by Cochrane). Additional search strategy details are provided in Table S1. 2.2. Study Selection The records were first reviewed by three independent authors based on the title and abstract (MHR, AP, and SG), all unrelated publications were removed and the full texts of the remaining articles were reviewed. Then, two independent reviewers (AP and SG) judged potentially eligible articles and disagreements were resolved by discussion and for each article a consensus was reached. 2.3. Eligibility and Inclusion Criteria The following predetermined conditions had to be met for studies to be considered for inclusion in this meta-analysis. For initial screening, all clinical studies were included in the systematic review, while RCT studies in phase I/II/III of COVID-19 vaccines were included in the meta-analysis. 2.4. Exclusion Criteria Non-randomized studies, studies without a placebo group, preclinical studies, studies on animal phase, meta-analyses, letters to the editor, review articles, studies with no extractable data, and news reports were excluded for the meta-analysis. However, nonrandomized studies were included only in the systematic review. Additionally, 11 vaccine studies (43 datasets) with no report in the type of adjuvants were excluded from the adjuvant side effect sub-group meta- analysis. 2.5. Data Extraction Four independent reviewers extracted data from the studies that were chosen. The following data were obtained from each article: first authors, trial initiation date, published year, vaccine name, company, study type, vaccine type, adjuvant, store temperature, trial phase, doses, injection interval (days), concentration, volume, trial country, all side effects, and efficacy-related data. Three of the authors (S.G, M.H.R, and A.P) extracted data independently, and another author (M.Z) reviewed extracted data at random; discrepancies were resolved by consensus. 2.6. Quality Assessment The JADAD scale (Oxford quality scoring system) for reporting quality of RCTs was used to evaluate the included articles’ quality. The JADAD scale included the three quality parameters of randomization, blinding, and account of all patients. Two questions are asked for the first two parameters, and one question is asked for the third parameter. Each query is given a score of one or zero. The highest acceptable score on the prepared checklist was five, with the lowest acceptable score being three. Data were derived from papers with a ranking of at least three (TableS2). Vaccines 2021, 9, 467 4 of 21 2.7. Analysis Initially, cleaning data and preparing them for analysis was done in Microsoft Office 365 and analysis was performed by Comprehensive Meta-Analysis Software Version 2.0 software. The point estimates of the effect size, odds ratios (ORs), and 95% confidence interval (95% CI) were calculated for estimating vaccine efficacy and side effects. Random effects models were used to estimate pooled effects. Additionally, to search for heterogeneity between studies, the I2 statistic was used [15] and high heterogeneity was characterized as an I2 > 50%, with sources of heterogeneity established through meta-regression and subgroup analyses. Subgroup analysis based on the vaccine phases significantly decreased the heterogeneity in the high heterogeneity cases. The presence and effect of publication bias were examined using funnel plots, Begg’s test, and Egger weighted regression methods [16,17]. For all analyses, two-tailed statistics and a significance level of less than 0.05 were considered. 3. Result 3.1. Characteristics of Included Studies A total of 32,790 publications were screened for the COVID-19 vaccines’ side effects and efficacies. Out of these studies, 27 met the systematic review’s inclusion criteria (non-randomized and randomized), while 25 randomized studies were included in the meta-analysis (Figure 1). Characteristics of the selected articles are summarized in Table 1. A total of 25 studies (123 datasets) were included in the meta-analysis. Studies with different vaccine phase reports, number of doses, injection concentration, different case, and control group numbers are considered a separate dataset for the meta-analysis. All included studies were written in English. Out of 25 randomized studies, 12 were double-blind, 2 participant-blind, 6 observer-blind, 3 single-blind, and 2 partially blind. The number of studies by vaccine platforms were 7 mRNA-based, 4 pro-subunit, 8 adenovirus-vector, 5 inactivated, and 1 VLPs. Vaccines 2021, 9, x FOR PEER REVIEW 4 of 23 query is given a score of one or zero. The highest acceptable score on the prepared checklist was five, with the lowest acceptable score being three. Data were derived from papers with a ranking of at least three (Table S2). 2.7. Analysis Initially, cleaning data and preparing them for analysis was done in Microsoft Office 365 and analysis was performed by Comprehensive Meta-Analysis Software Version 2.0 software. The point estimates of the effect size, odds ratios (ORs), and 95% confidence interval (95% CI) were calculated for estimating vaccine efficacy and side effects. Random effects models were used to estimate pooled effects. Additionally, to search for heterogeneity between studies, the I2 statistic was used [15] and high heterogeneity was characterized as an I2 > 50%, with sources of heterogeneity established through meta-regression and subgroup analyses. Subgroup analysis based on the vaccine phases significantly decreased the heterogeneity in the high heterogeneity cases. The presence and effect of publication bias were examined using funnel plots, Begg’s test, and Egger weighted regression methods [16,17]. For all analyses, two-tailed statistics and a significance level of less than 0.05 were considered. 3. Result 3.1. Characteristics of Included Studies A total of 32,790 publications were screened for the COVID-19 vaccines’ side effects and efficacies. Out of these studies, 27 met the systematic review’s inclusion criteria (nonrandomized and randomized), while 25 randomized studies were included in the metaanalysis (Figure 1). Characteristics of the selected articles are summarized in Table 1. A total of 25 studies (123 datasets) were included in the meta-analysis. Studies with different vaccine phase reports, number of doses, injection concentration, different case, and control group numbers are considered a separate dataset for the meta-analysis. All included studies were written in English. Out of 25 randomized studies, 12 were double-blind, 2 participant- blind, 6 observer-blind, 3 single-blind, and 2 partially blind. The number of studies by vaccine platforms were 7 mRNA-based, 4 pro-subunit, 8 adenovirus-vector, 5 inactivated, and 1 VLPs. Figure

  1. Flow diagram of literature search and study selection for meta-analysis (PRISMA flow chart). Figure
  2. Flow diagram of literature search and study selection for meta-analysis (PRISMA flow chart).

Vaccines 2021, 9, 467 5 of 21 Table 1. Characterization of included studies. Study Trial Initiation Date Pub. Year Vaccine Name Company Study Type Vaccine Type Adjuvant Store Temp ( ◦C) RCT Phase Dose (s) Age Range (Year) Injection Interval (Days) Concentration Trial Country Ref Yang et al. 22 Juneand 3 July 2020 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo-controlled Pro-Subunit Aluminum hydroxide 2–8 I 3 22.9–54.7 30 25 µg * China [18] Yang et al. 22 June and 3 July 2020 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo-controlled Pro- Subunit Aluminum hydroxide 2–8 I 3 20.9–49.4 30 50 µg * China [18] Ella et al. 13 and 30 July 2020 2021 BBV152 (Covaxin) Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel-IMDG 2–8 I 2 18–55 14 3 µg * India [19] Ella et al. 13 and 30 July 2020 2021 BBV152 (Covaxin) Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel-IMDG 2–8 I 2 18–55 14 6 µg * India [19] Ella et al. 13 and 30 July 2020 2021 BBV152 (Covaxin) Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel 2–8 I 2 18–55 14 6 µg* India [19] Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non-randomized Adenovirusbased No adjuvant UN I 1 18–60 No 5 × 101 0 VP * China [20] Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non- randomized Adenovirusbased No adjuvant UN I 1 18–60 No 1 × 1011 VP * China [20] Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non-randomized Adenovirusbased No adjuvant UN I 1 18–60 No 1.5 × 1011 VP * China [20] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 20–50 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 24–53 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo- controlled Pro-Subunit AS03 2–8 I 2 55–70 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 20–53 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–71 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 20–54 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 21–53 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo- controlled Pro-Subunit AS03 2–8 I 2 55–64 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 19–55 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–67 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 18–49 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 19–47 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo- controlled Pro-Subunit AS03 2–8 I 2 55–63 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 21–50 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–74 21 30 µg * Australia [21] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 18–60 28 2 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 19–59 28 4 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 20– 59 28 6 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 20–59 28 8 µg * Germany [22] Kremsner et

  1. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based Noadjuvant 5 I 2 19–59 28 12 µg * Germany [22] Ward et al. July, 2020 2020 CoVLP Medicago

Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 15 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 15 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 15 µg Canada [23] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 25 µg * United States [24] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 100 mg * United States [24] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 250 mg * United States [24] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 56–70 28 25 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA- based No adjuvant −20 I 2 71≤ 28 25 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 56–70 28 100 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 71≤ 28 100 mg * United States [25] Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 18–59 21 25 µg/0.6 ml Australia, United States [26] Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 2 18–59 21 5 µg/0.6 ml Australia, United States [26] Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 2 18–59 21 25 µg/0.6 ml Australia, United States [26] Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 1 18–59 21 25 µg/0.6 ml Australia, United States [26] Vaccines 2021, 9, 467 6 of 21 Table 1. Cont. Study Trial Initiation Date Pub. Year Vaccine Name Company Study Type Vaccine Type Adjuvant Store Temp ( ◦C) RCT Phase Dose (s) Age Range (Year) Injection Interval (Days) Concentration Trial Country Ref Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 1 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 21.4–55.8 21 10 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 25.1–55 21 30 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 23.9–54 21 50 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 1 19.9–47.8 No 60 µg * Germany [27] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 20.9–53.2 21 10 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)– (−80) I 2 18–55 21 10 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based Noadjuvant (−60)–(−80) I 2 65–85 21 20 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA- based No adjuvant (−60)–(−80) I 2 18–55 21 20 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 30 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo- controlled mRNA-based No adjuvant (−60)–(−80) 1 2 18–55 21 30 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 10 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 10 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 20 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)– (−80) I 2 18–55 21 20 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 30 µg * United States, Germany [28] Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA- based No adjuvant (−60)–(−80) I 2 18–55 21 30 µg * United States, Germany [28] Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 3 65–85 28 2.5 µg * China [29] Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 3 18–59 28 5 µg * China [29] Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 3 18–59 28 10 µg * China [29] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 2 µg * China [30] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 2 µg * China [30] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double- blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 60 ≤ 28 4 µg * China [30] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 4 µg * China [30] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 60 ≤ 28 8 µg * China [30] Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 8 µg * China [30] Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 60≤ 14 3 µg * China [31] Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double- blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 3 µg * China [31] Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 14 6 µg * China [31] Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 I 2 18–59 28 6 µg * China [31] Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized Adenovirusbased No adjuvant 2–8 I 1 18–59 No 1011 VP * Russia [32] Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized Adenovirusbased No adjuvant 2–8 I 1 18–60 No 1011 * Russia [32] Vaccines 2021, 9, 467 7 of 21 Table 1. Cont. Study Trial Initiation Date Pub. Year Vaccine Name Company Study Type Vaccine TypeAdjuvant Store Temp ( ◦C) RCT Phase Dose (s) Age Range (Year) Injection Interval (Days) Concentration Trial Country Ref Logunov et al. 18 June and 3 August 2020 2020 Sputnik V (Lyo) Gamaleya Non-randomized Adenovirusbased No adjuvant 2–8 I 1 18–60 No 1011 * Russia [32] Logunov et al. 18 June and 3 August 2020 2020 Sputnik V (Lyo) Gamaleya Non-randomized Adenovirusbased No adjuvant 2–8 I 1 18–60 No 1011 * Russia [32] Folegatti et al. 23 April and 21 May 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 I/II 2 18–60 28 5 × 101 0 VP * United Kingdom [33] Mulligan et al. 4 May and 19 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo- controlled mRNA-based No adjuvant (−60)–(−80) I/II 2 18–55 21 10 µg * Multicenter 1 [34] Mulligan et al. 4 May and 19 June,2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I/II 2 24–42 21 30 µg * Multicenter 1 [34] Mulligan et al. 4 May and 19 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I/II 1 23–52 No 100 µg * Multicenter 1 [34] Yang et al. 12 and 17 July 2020 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo-controlled Pro-Subunit Aluminum hydroxide 2–8 II 2 25–53 30 25 µg * China [18] Yang et al. 12 and 17 July 2021 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo- controlled Pro-Subunit Aluminum hydroxide 2–8 II 2 18.8–58.4 30 50 µg * China [18] Yang et al. 12 and 17 July 2022 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo-controlled Pro-Subunit Aluminum hydroxide 2–8 II 3 19.9–59.1 30 25 µg * China [18] Yang et al. 12 and 17 July 2023 2020 ZF2001 Anhui Zhifei Longcom Randomized, double-blind, placebo-controlled Pro-Subunit Aluminum hydroxide 2–8 II 3 20–59.7 30 50 µg * China [18] Zhu et al. 11 and 16 April 2020 2020 Ad5- nCoV CanSino Randomized, double-blind, placebo-controlled Adenovirusbased No adjuvant UN II 1 19.3–59.6 No 1 × 1011 * China [35] Zhu et al. 11 and 16 April 2020 2020 Ad5-nCoV CanSino Randomized, double-blind, placebo-controlled Adenovirusbased No adjuvant UN II 1 18≤ No 5 × 101 0 * China [35] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer- blind, placebo-controlled mRNA-based No adjuvant −20 II 2 18≤ 28 50 mg * United States [36] Chu et

  1. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-

controlled mRNA-based No adjuvant −20 II 2 18–54.99 28 50 mg * United States [36] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 55≤ 28 100 mg * United States [36] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 18–54.99 28 100 mg * United States [36] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 55≤ 28 2.2 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 1 18–55 No 2.2 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 56–69 28 2.2 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 1 56–69 No 2.2 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 70≤ 28 2.2 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 70≤ 28 3.5–6.5 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 1 18–55 No 3.5–6.5 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 56–69 28 3.5–6.5 × 101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 1 56–69 No 3.5–6.5 ×101 0 VP * United Kingdom [37] Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca Randomized, participant-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II 2 70≤ 28 3.5–6.5 × 101 0 VP * United Kingdom [37] Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double- blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 3 70≤ 28 5 µg * China [29] Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 3 18–59 28 5 µg * China [29] Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 1 18–59 No 8 µg * China [30] Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 14 4 µg * China [30] Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 21 4 µg * China [30] Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 28 4 µg * China [30] Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 14 3 µg * China [31] Vaccines 2021, 9, 467 8 of 21 Table 1. Cont. Study Trial Initiation Date Pub. Year Vaccine Name Company Study Type Vaccine Type Adjuvant Store Temp ( ◦C) RCT Phase Dose (s) Age Range (Year) Injection Interval (Days) Concentration Trial Country Ref Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 28 3 µg * China [31] Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 14 6 µg * China [31] Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated Aluminum hydroxide 2–8 II 2 18–59 28 6 µg * China [31] Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized Adenovirusbased No adjuvant 2–8 II 2 18–59 21 1011 VP * Russia [32] Logunov et al. 18 June and 3 August 2020 2020 Sputnik V (lyophilised) Gamaleya Non- randomized Adenovirusbased No adjuvant 2–8 II 2 18–60 21 1011 VP * Russia [32] Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo- controlled Adenovirusbased No adjuvant 2–8 II/III 2 18–60 28 2.2 × 101 0 VP * (1st)/5 × 101 0 VP * (2nd) United Kingdom [38] Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 II/III 2 18≤ 28 5 × 101 0 VP * United Kingdom [38] Pollack et al. 27 July and 14 November 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) II/III 2 18≤ 21 30 µg/0.3 ml Multinational 1 [39] Baden et al. 27 July and 23 October 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 III 2 16–89 28 100 µg * United States [40] Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo-controlled Adenovirusbased No adjuvant 2–8 III 2 18–95 28 5 × 101 0 VP * Brazil [38] Logunov et al. 7 September and 24 November 2020 2021 Sputnik V Gamaleya Randomized, double-blind, placebo controlled Adenovirusbased No adjuvant 2–8 III 2 18≤ 21 1011 VP * Russia [41] Sadoff et al. 20 July 2020 2021 Ad26.COV2.S Johnson & Johnson Randomized, double-blind, placebo-controlled Adenoviral vector No adjuvant UN I/II 2 18–55 No 5 × 1010 Belgium, US [42] Sadoff et al. 20 July 2020 2021 Ad26.COV2.S Johnson & Johnson Randomized, double-blind, placebo-controlled Adenoviral vector No adjuvant UN I/II 2 19–55 No 1 × 1011 Belgium, US [42] Sadoff et al. November 2020 2021 Ad26.COV2.S Johnson & Johnson Randomized, double-blind, placebo-controlled Adenoviral vectorNo adjuvant UN I/II 2 65–83 No 5 × 1010 Belgium, US [42] Sadoff et al. November 2020 2021 Ad26.COV2.S Johnson & Johnson Randomized, double-blind, placebo-controlled Adenoviral vector No adjuvant UN I/II 2 65–88 No 1 × 1011 Belgium, US [42] 1 From 152 sites worldwide (United States, 130 sites; Argentina, 1; Brazil, 2; South Africa, 4; Germany, 6; and Turkey, 9). UN = unavailable. VP = virus particle; Pro-Subunit = protein subunit; VLP = virus-like particle; Alum = aluminium; Adv= adenovirus; CpG = cytosine-guanine oligodeoxynucleotide; AS03= squalene-based immunologic adjuvant; Algel-IMDG (an imidazoquinoline molecule chemisorbed on alum [Algel]); RCT = randomized control trial. * per 0.5 m. Studies with different reports for the vaccine phase, the vaccine dose, injection concentration, different case, and control group numbers are considered as a separate dataset. More detailed information is provided in Table S3. Vaccines 2021, 9, 467 9 of 21 3.2. Characteristics of Participants A total of 58,889 cases that received the COVID-19 vaccine and 46,638 controls who received placebo were included in this study. Out of 58,889 vaccine cases, 31,070 were male and 27,819 female. Out of 46,638 individuals in the placebo group, 33,354 were male and 13,284 female. All vaccines and placebos were intramuscularly (IM) injected. Detailed information of age ranges of either vaccine or placebo groups is shown in Table 1. 3.3. Efficacy of Different COVID- 19 Vaccines 3.3.1. Efficacy of mRNA-Based COVID-19 Vaccines The mRNA-based COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) efficacy in a total of 34,041 cases in phase II/III RCTs (Table 2). Figure 2 shows the efficacy of COVID-19 vaccines after the first and second doses. Efficacy four weeks after first dose was reported for only one antibody (NAb 70.2% (95% CI 0.655–0.746)). Efficacy after a second dose of mRNA-based COVID-19 vaccines was reported for RBD, S-protein, and NAbs, with the highest efficacy for NAbs at 99.5% (95% CI 0.980–0.999) (Table 3). Table 2. Efficacy of adenovirus- based and mRNA-based COVID-19 vaccines. Vaccine Type RCT Phase Number Studies Efficacy (%) 95% CI (%) Included Case N Heterogeneity Test, p-Value Lower Limit Upper Limit Adenovirus-based 2/3 4 80.2 0.564 0.927 20771 < 50%), which indicates that variation in study outcomes between the included studies was low, even though different companies and different research groups across the world have been included. More detailed information such as Forest plot, Funnel plot, heterogeneity test, and sub-group analysis of each side effects are shown in Figures S1–S21 (in the Supplementary Materials). Vaccines 2021, 9, 467 11 of 21 Table 3. Efficacy of different COVID-19 vaccines after the first and second doses. Vaccine Placebo Shot Antigen/ Antibody After Injection (Week) Vaccine Type Studies N Efficacy Lower Limit Upper Limit I-Squared Studies N Efficacy Lower Limit Upper Limit I- Squared After 1st dose RBD 2 Adenovirus-based 4 0.603 0.471 0.722 73.8 2 0.004 0.001 0.027 0 Inactivated 4 0.870 0.734 0.983 93.8 4 0.024 0.008 0.072 0 3 Adenovirus-based 2 0.976 0.939 0.997 0.0 NA NA NA NA NA VLP 8 0.238 0.091 0.375 84.3 NA NA NA NA NA 4 Adenovirus-based 2 0.966 0.942 0.980 0.0 2 0.004 0.001 0.027 0 Inactivated 4 0.913 0.564 0.958 90.7 4 0.061 0.033 0.110 0 Pro- Subunit 6 0.628 0.590 0.665 0.0 NA NA NA NA NA S-protein 2 Inactivated 2 0.293 0.182 0.437 0.0 2 0.083 0.032 0.202 0 3 Pro-Subunit 4 0.790 0.474 0.874 91.0 4 0.021 0.005 0.079 0 4 Inactivated 2 0.396 0.269 0.539 0.0 2 0.021 0.003 0.134 0 Pro-Subunit 4 0.873 0.671 0.892 91.9 4 0.021 0.005 0.079 0 NAb 2 Inactivated 4 0.583 0.210 0.868 95.0 4 0.030 0.013 0.070 0 3 Pro-Subunit 4 0.551 0.291 0.786 85.0 4 0.021 0.005 0.079 0 4 Adenovirus-based 2 0.547 0.496 0.596 76.8 2 0.008 0.002 0.031 0 Inactivated 4 0.691 0.537 0.812 95.0 4 0.025 0.008 0.074 0 mRNA-based 4 0.702 0.655 0.746 73.9 4 0.010 0.004 0.026 0 After 2nd dose RBD 2 Inactivated 9 0.929 0.876 0.960 61.8 9 0.171 0.077 0.336 85 mRNA-based 5 0.731 0.532 0.866 86.0 NA NA NA NA NA 3 Adenovirus-based 3 0.982 0.980 0.984 0.0 1 0.149 0.139 0.159 0 VLP 9 0.787 0.581 0.908 78.1 NA NA NA NA NA 4 Inactivated 4 0.944 0.842 0.982 15.9 4 0.063 0.026 0.143 0 Pro-Subunit 6 0.956 0.937 0.970 0.0 NA NA NA NA NA S- protein 2 Inactivated 7 0.941 0.877 0.973 61.4 7 0.290 0.139 0.507 87 Pro-Subunit 18 0.852 0.719 0.928 62.4 18 0.028 0.014 0.052 0 mRNA-based 5 0.786 0.725 0.836 0.0 NA NA NA NA NA 4 Inactivated 4 0.934 0.842 0.974 15.9 4 0.063 0.026 0.143 0 Pro-Subunit 14 0.792 0.679 0.873 50.7 15 0.031 0.015 0.061 0 NAbs 2 Adenovirus-based 1 0.999 0.985 1.000 0.0 NA NA NA NA NA Inactivated 90.845 0.724 0.919 86.5 9 0.151 0.068 0.303 85 Pro-Subunit 23 0.753 0.667 0.823 68.2 19 0.028 0.015 0.052 0 mRNA-based 9 0.870 0.747 0.938 82.4 4 0.008 0.003 0.024 0 3 Adenovirus-based 1 0.958 0.955 0.961 0.0 1 0.071 0.065 0.079 0 4 Adenovirus-based 1 0.999 0.985 1.000 0.0 NA NA NA NA NA Inactivated 4 0.700 0.375 0.901 86.1 4 0.033 0.011 0.099 0 Pro-Subunit 17 0.759 0.574 0.881 62.9 15 0.031 0.015 0.061 0 mRNA-based 4 0.995 0.980 0.999 0.0 4 0.016 0.007 0.035 0 S-protein = spike protein, Alum = aluminium, CpG = cytosine-guanine oligodeoxynucleotide, AS03 = squalene-based immunologic adjuvant, RBD = receptor-binding domain, NAb = neutralizing antibody, Pro-Subunit = protein subunit, NA = not available. Vaccines 2021, 9, 467 12 of 21 Vaccines 2021, 9, x FOR PEER REVIEW 14 of 23 Figure 3. Local and systemic side effects of different COVID-19 vaccines. The administration of mRNA-based vaccine was associated with a greater number of side effects, such as injection site pain, fever, redness, swelling, induration, pruritus, chills, myalgia, arthralgia, vomiting, fatigue, and headache, by yielding a summary OR of 83.06 (95% CI 37.05–186.1) (in phase II/III RCTs), 36.90 (95% CI 12.34–105.21) (in phase I/II/III RCTs), 24.40 (95% CI 18.73–31.77) (in phase I/II/III RCTs), 18.79 (95% CI 4.87–72.40) (in phase I/II/III RCTs), 17.5 (95% CI 1.96–155.58) (in phase I/II RCTs), 17.50 (95% CI 1.98– 155.58) (in phase II/III RCTs), 13.11 (95% CI 7.19–23.89) (in phase II/III RCTs), 10.71 (95% CI 6.51–17.60) (in phase I/II RCTs), 9.67 (95% CI 1.27–76.90) (in phase III/II RCTs), 8.71 (95% CI 4.38–17.34) (in phase I/II RCTs), 6.16 (95% CI 5.86–6.48) (in phase III RCTs), and 5.13 (95% CI 2.32– 11.31) (in phase I/II RCTs), respectively, compared to other types of vaccines. Nevertheless, the adenovirus-vectored vaccine was associated with higher rates of diarrhea with OR of 4.59 (95% CI 3.58–5.89), and arthralgia OR of 10.61 (95% CI 7.60–14.83) compared to others (Table 4). It should be considered that heterogeneity (I-squared test) of the pooled meta-analysis for most of the side effects was low (I2 < 50%), which indicates that variation in study outcomes between the included studies was low, even though different companies and different research groups across the world have been included. More detailed information such as Forest plot, Funnel plot, heterogeneity test, and subgroup analysis of each side effects are shown in Figures S1–S21 (in the Supplementary Materials). Figure 3. Local and systemic side effects of different COVID-19 vaccines. Table 4. Association of side effects with different COVID-19 vaccines. Side Effect Vaccine Type Phase Odds Ratio (95% CI) Included Study Heterogeneity Test, I-Squared Site pain mRNA-based 2/3 83.06 (37.05– 186.1) 5 81.33 1/2 28.26 (16.18–49.35) 17 0 Adenovirus-based 2/3 13.64 (8.39–22.17) 2 0 1/2 3.2 (2.7–4) 2 0 Inactivated 2/3 1.73 (0.667–4.5) 6 46.64 1/2 3.19 (1.3–7.6) 10 52.14 Pro-Subunit 2/3 2.14 (1.01–4.5) 4 48.55 1/2 2.29 (0.48–10.8) 2 29.93 Swelling Adenovirus-based 1/2/3 1.21 (0.77–1.89) 2 0 Inactivated 1/2/3 0.402 (0.056–2.90) 2 0 Pro-Subunit 1/2/3 6.48 (3.09–13.67) 5 0 mRNA-based 1/2/3 18.79 (4.87–72.40) 3 59.08 Redness Adenovirus-based 1/2/3 1.35 (0.815–2.25) 4 0 Pro-Subunit 1/2/3 7.29 (3.70–14.38) 6 0 mRNA-based 1/2/3 24.40 (18.73–31.77) 1 0 Itch Adenovirus-based 1/2 3.10 (1.96–4.89) 1 0 Inactivated 1/2 0.32 (0.02–5.3) 1 0 Pro-Subunit 1/2 25.44 (7.85–82.40) 6 0 Vaccines 2021, 9, 467 13 of 21 Table 4. Cont. Side Effect Vaccine Type Phase Odds Ratio (95% CI) Included Study Heterogeneity Test, I-Squared Cough Adenovirus-based 1/2/3 1.76 (1.20–2.58) 3 0 Fever Adenovirus-based 1/2/3 1.73 (0.57–5.66) 3 90.5 Inactivated 1/2/3 0.27 (0.09–0.76) 5 0 Pro-Subunit 1/2/3 1.17 (0.73–1.86) 4 0 mRNA-based 1/2/3 36.90 (12.34–105.21) 3 43.31 Headache mRNA-based 3 4.63 (4.4–4.86) 1 0 2 2.32 (1.28–4.19) 4 69.20 1/2 5.13 (2.32–11.31) 5 63.02 Adenovirus-based 2 2.54 (1.65–3.91) 2 0 1/2 3.01 (2.35–3.87) 1 0 3 0.58 (0.49–0.68) 1 0 Inactivated 2 0.18 (0.02–1.14) 2 0 Pro-Subunit 2 1.25 (0.33–4.7) 2 0 1/2 1.99 (1.21–3.26) 14 0 Fatigue Adenovirus-based 1/2 2.72 (2.2– 3.37) 3 0 Inactivated 1/2 0.39 (0.18–0.82) 7 0 Pro-Subunit 1/2 2.7 (1.01–7.16) 4 37.2 mRNA-based 1/2 5.0 (3.42–7.33) 24 48.23 2–3 4.87 (4.65–5.09) 1 0 3 6.16 (5.86–6.48) 1 0 Induration Adenovirus-based 1/2 0.16 (0.05–0.49) 2 46.44 Inactivated 1/2 0.18 (0.06–0.58) 4 0 Pro-Subunit 1/2 2.62 (1.23–5.58) 2 0 mRNA-based 1/2 17.5 (1.96–155.58) 1 0 Vomiting Adenovirus-based 1/2 2.75 (1.99–3.82) 3 0 Inactivated 1/2 0.32 (0.02–5.38) 1 0 mRNA-based 1/2 8.71 (4.38–17.34) 8 0 2–3 4.87 (4.65–5.09) 1 0 3 6.16 (5.86–6.48) 1 0 Diarrhea Adenovirus-based 1/2 2.51 (1.12–5.63) 2 0 Inactivated 1/2 0.60(0.13–2.83) 3 0 mRNA-based 1/2 0.54 (0.27–1.10) 5 0 Myalgia Adenovirus-based 1/2 4.59 (3.58–5.89) 3 0 Inactivated 1/2 1.43 (0.25–8.08) 2 0 Pro-Subunit 2.92 (0.57–8.75) 8 53.30 mRNA-based 1/2 10.71 (6.51–17.60) 10 33.74 2/3 7.0 (6.57–7.47) 1 0 3 1.43 (0.25–8.08) 1 0 Arthralgia Adenovirus-based 2/3 4.06 (2.99–5.57) 3 0 Pro-Subunit 2/3 1.34 (0.47–3.83) 4 4.833 mRNA-based 2/3 9.67 (1.27–76.90) 3 67.97 Chills Adenovirus-based 2/3 10.61 (7.60–14.83) 1 0 mRNA-based 2/3 13.11 (7.19–23.89) 8 3.82 Pruritus Adenovirus-based 2/3 0.54 (0.23–1.25) 2 0 mRNA-based 2/3 17.50 (1.98–155.58) 1 0 Vaccines 2021, 9, 467 14 of 21 Serious Adverse Side Effects of COVID-19 Vaccines Only three studies reported anaphylactic shock as an adverse effect of COVID-19 vaccines—(1) 1 out of 84 vaccine cases for the inactivated vaccine [30]; (2) 1 case out of 2063 vaccinated for the adenovirus-based vaccine [38], (3) 1 case out of 15,181 in the vaccine group, and 1 case out of 15,170 in the placebo group, for the mRNA-based vaccine [40]. A total of 37 blot clots, including 22 pulmonary embolus cases (PE) and 5 deep vein thrombosis (DVT), have been reported for the Oxford-AstraZeneca vaccine among 17 million people in the EU and Britain [43]; see discussion for recent contributions. The number of clotting events is not greater than what is seen in the general population, with no indication that there is a causal effect. 3.5. Side Effects of COVID-19 Vaccines Based on Different Adjuvants The sub- group analysis was assessed to estimate the potential side effects of COVID-19 vaccines based on the different types of administrated adjuvants. Interestingly, in all cases, potassium aluminum sulfate (alum) had the smallest number of systemic and local side effects compared to other adjuvants or vaccines without adjuvant, except injection site redness, of which vaccines without adjuvant had higher rates of site redness (Figure 4). Accordingly, vaccines with alum adjuvant had lower systemic side effects of fatigue OR 0.392 (95% 0.18–0.82), vomiting 0.325 (95% 0.02–5.30), fever 0.85 (95% 0.51–1.43), myalgia 1.43 (95% 0.25–8.0), diarrhea 0.608 (95% 0.13–2.87), and injection site pain 2.40 (95% 1.51–3.83) between different adjuvants and vaccines with no adjuvant (Table 5). The vaccine with no adjuvant was associated with higher redness OR 0.923 (95% 0.23–3.6). Itch OR 13.20 (95% 3.23–53.90) and swelling OR of 3.83 (95% 1.52–9.64) was only reported for vaccines with alum adjuvant. For more detailed information see Figures S22–S30. Vaccines 2021, 9, x FOR PEER REVIEW 17 of 23 CpG/Alum 2/3 2.42 (0.13–44.50) 1 0 Matrix-M1 2/3 1.57 (0.26–9.4) 3 67.96 No adjuvant 2/3 9.66 (3.97–23.47) 8 49.99 Diarrhea Alum 2/3 0.608 (0.13–2.87) 3 0 No adjuvant 2/3 0.89 (0.40–1.97) 6 50.47 Local Injection site pain Alum 2/3 2.40 (1.51–3.83) 22 44.55 No adjuvant 2/3 25.61 (13.31– 49.30) 7 36.60 Itch Alum 2/3 13.20 (3.23–53.90) 7 40.58 Swelling Alum 2/3 3.83 (1.52–9.64) 7 37.52 Redness Alum 2/3 7.29 (3.7–14.39) 6 0 No adjuvant 2/3 0.923 (0.23–3.6) 2 0 Alum = aluminum, CpG = cytosine-guanine oligodeoxynucleotide, AS03 = squalene-based immunologic adjuvant. Figure 4. Association of adjuvant side effects of different COVID-19 vaccines. 4. Discussion The purpose of vaccination is to protect individuals from infection and transmission. Although the emergency use authorization for some of the COVID-19 vaccines has been approved by the Food and Drug Administration in the US and the Department of Health and Human Services of each country, the vaccines’ efficacy and side effects have not yet been comprehensively discussed, although popular media and politicians have made many unsubstantiated claims. Therefore, in the current meta- analysis, we provide systematic and comprehensive data regarding the vaccines’ safety, efficacy, and immunogenicity against SARS-CoV-2. Here, we mainly focused on available RCTs publications on the safety, efficacy, and immunogenicity of COVID-19 vaccines. Figure 4. Association of adjuvant side effects of different COVID-19 vaccines. Vaccines 2021, 9, 467 15 of 21 Table 5. Side effects of COVID- 19 vaccines based on different adjuvant types. Side Effect Adjuvant Type Phase Odds Ratio (95% CI) Included Study Heterogeneity Test, I-Squared Systemic Fatigue Alum 2/3 0.392 (0.18–0.82) 7 0 Matrix-M1 2/3 3.70 (1.36–10.02) 3 24.81 No adjuvant 2/3 4.43 (2.62–7.49) 6 54.08 Vomiting Alum 2/3 0.325 (0.02–5.30) 1 0 No adjuvant 2/3 3.46 (1.45–8.26) 7 0 Fever Alum 2/3 0.85 (0.51–1.43) 9 20.78 No adjuvant 2/3 2.96 (1.22–7.17) 2 68.19 Myalgia Alum 2/3 1.43 (0.25–8.0) 2 0 AS03 2/3 14.331 (3.39–60.56) 3 0 CpG/Alum 2/3 2.42 (0.13–44.50) 1 0 Matrix-M1 2/3 1.57 (0.26–9.4) 3 67.96No adjuvant 2/3 9.66 (3.97–23.47) 8 49.99 Diarrhea Alum 2/3 0.608 (0.13–2.87) 3 0 No adjuvant 2/3 0.89 (0.40–1.97) 6 50.47 Local Injection site pain Alum 2/3 2.40 (1.51–3.83) 22 44.55 No adjuvant 2/3 25.61 (13.31–49.30) 7 36.60 Itch Alum 2/3 13.20 (3.23–53.90) 7 40.58 Swelling Alum 2/3 3.83 (1.52– 9.64) 7 37.52 Redness Alum 2/3 7.29 (3.7–14.39) 6 0 No adjuvant 2/3 0.923 (0.23–3.6) 2 0 Alum = aluminum, CpG = cytosine-guanine oligodeoxynucleotide, AS03 = squalene-based immunologic adjuvant. 4. Discussion The purpose of vaccination is to protect individuals from infection and transmission. Although the emergency use authorization for some of the COVID-19 vaccines has been approved by the Food and Drug Administration in the US and the Department of Health and Human Services of each country, the vaccines’ efficacy and side effects have not yet been comprehensively discussed, although popular media and politicians have made many unsubstantiated claims. Therefore, in the current meta-analysis, we provide systematic and comprehensive data regarding the vaccines’ safety, efficacy, and immunogenicity against SARS-CoV-2. Here, we mainly focused on available RCTs publications on the safety, efficacy, and immunogenicity of COVID-19 vaccines. The present study was carefully surveyed for the general and specific target antigen efficacy of each vaccine group. Our analysis showed that variation in the efficacy of vaccines after the first doses are remarkable in comparison with the efficacies after the second doses. Therefore, enrollment of the second dose should produce a more reliable outcome and efficacy compared to a single dose. In total, mRNA-based COVID-19 vaccines had 94.6% efficacy. The RNA-based vaccine elicited high levels of NAbs after one month of the first (70%) and second (99.5%) doses. Unfortunately, data for the RNA- based vaccines against RBD antigen were not available after the first dose. Protection against variants has been shown with the mRNA-based vaccine against the United Kingdom (B.1.1.7, also called 20I/501Y.V1) variant [44,45], but they may be less effective against the variant first detected in South Africa (B.1.351, known as 20H/501Y.V2) [46]. A week after the second dose of mRNA-based vaccine, induction of neutralizing antibody titers in the serum sample was 6- fold lower for participants bearing B.1.351 variant compared to original Wuhan-Hu-1 spike protein [47]. The B.1.351 variant carries two substitutions within the S-protein, which can escape three classes of therapeutically relevant antibodies. These data indicate reinfection with antigenically distinct variants and mitigates the full efficacy of spike-based COVID-19 vaccines [48]. Vaccines 2021, 9, 467 16 of 21 From our summary analysis, the total efficacy of the adenovirus-vectored COVID-19 vaccines was 80.2%. The highest efficacy after a single dose is reported with the adenovirusvectored COVID- 19 vaccines, with very low variation and CI against RBD at 3 weeks (96.7%) and 4 weeks (96.6%) after vaccination compared to placebo controls. Some of the adenovirus-vectored COVID-19 vaccines, such as Johnson & Johnson, need just one dose, with the efficacy against RBD being a possible reason. However, based on the rollout timeline, long-term (more than four weeks) efficacy of adenovirus- vectored COVID-19 vaccines was not reported by any of the RCTs. For the other vaccine types, total efficacy has not been reported, only the antigen-specific efficacy was reported in these RCTs. The pro-subunit vaccine had the highest efficacy against spike antigen at 1 month after the first injection. The efficacy of the VLP vaccines was lower than other COVID-19 vaccines and reported only against RBD after the first (23.8%) and second dose (78.7%). All reports for VLP vaccines are from RCT phase I trials, and the lower efficacy of these vaccines may be the most probable reason. Any vaccine is expected to cause temporary side effects caused by activation of an immune response and injection site tissue trauma. Uptake of vaccines is related to perceived and real adverse side effects, both short-term and long-term. In this study, adjusted pooled odds ratios between vaccine and placebo groups indicated that RNA-based vaccines had higher rates of side effects in reactogenicity, including site pain, swelling, redness, fever, headache, fatigue, induration, vomiting, myalgia, chills, and pruritus (Table 2). No sign of cough or itch was found in RNA-based vaccines, and lower rates of diarrhea and arthralgia were observed for this vaccine. By avoiding negativity bias, this might provide strong evidence of RNA-based vaccines’ effectiveness, by eliciting a more robust immune responsethan other vaccine groups. Additionally, the rate of serious adverse side effects such as anaphylactic shock, an allergic reaction, was not remarkable with this vaccine, with only one case reported in both the vaccine and placebo groups [40]. In the context of side effects, the adenovirus-vectored vaccines are associated with increased diarrhea and arthralgia in comparison with other vaccines, see Table 2. A recent systematic review and meta-analysis by Yuan et al. [49] showed no significant difference in systemic reactions, with only local side effects, including pain, itching, and redness, being reported [49]. One case of anaphylactic shock was reported for this vaccine [38]. Several pulmonary emboli (PE) and deep vein thrombosis (DVT) cases have been reported as rare events for the Oxford- AstraZeneca vaccine, causing a temporary suspension of this vaccine’s use in many countries and age-specific rollout in others. However, to date, the data are too weak and anecdotal to provide clear evidence of cause and effect [50]. Similarly, the Johnson & Johnson vaccine was also temporarily suspended in April 2021 by the FDA, as several people developed rare blood-related problems of thrombosis with thrombocytopenia syndrome leading to cerebral venous sinus thrombosis (CVST) [51]. A DVT has also been reported shortly after the second dose of an mRNA-based vaccine as well [52]. Anaphylaxis as an acute allergic reaction has also been reported as a rare event for some vaccines, such as mRNA COVID-19 vaccines [53] and adenovector vaccines against COVID-19 [54]. Overall, these severe life-threatening adverse events are occurring rarely, thus supporting the ongoing rollout of global vaccination programs. Data are currently emerging on Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) following vaccination with COVID-19 vaccines [55]. VITT presents with symptoms of thromboembolism and especially signs of thrombocytopenia, cerebral blood clots, or abdominal or arterial clots, such as easy bruising, bleeding or new and/or severe headaches, and pain in the abdomen or a painful, cold numb extremity, particularly with onset 4 to 28 days after immunization. This is due to thrombosis (blood clots) involving the cerebral venous sinuses, or CVST (large blood vessels in the brain), and other sites in the body (including but not limited to the large blood vessels of the abdomen and the veins of the legs) along with thrombocytopenia, or low blood platelet counts. These events are rare, but to date have been documented for the mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) and the adenoviral vector vaccines ChAdOx1 nCoV-19 vaccine Vaccines 2021, 9, 467 17 of 21 (Astra Zeneca) and Ad26. COV2-S vaccine (Janssen; Johnson & Johnson). Given the very recent emergence, our meta study does not include an analysis of VITT. Co-administration of vaccine with adjuvants is being used in VLP subunit vaccines and certain inactivated vaccines [55]. Adjuvants have an essential role owning to inducing specific immune responses, IgG1, and NAbs titers. It also considers potential dose-sparing of CoV vaccine [56]. Multiple adjuvants, such as alum salts, emulsions, and TLR agonists have been formulated for SARS-CoV, SARS-CoV-2, and MERS-CoV [55]. The potential side effects of COVID-19 vaccines based on the different types of adjuvants investigated showed that alum- adjuvanted CoV vaccines had the lowest systemic side effects among other adjuvants or non- adjuvant in Table 3. The non-adjuvanted vaccines revealed immunopathologic reactions including high fatigue, vomiting, fever, myalgia, and diarrhea and redness, while alum-adjuvanted CoV vaccines showed itch and swelling. Overall, the metadata obtained in this study demonstrated that the alum- adjuvanted CoV vaccines had the smallest number of issues compared with other adjuvants and the non-adjuvant formulations. The limitations of this study are: 1. The overall effectiveness and antigen- specific efficacy of some vaccines have not been reported after the first or second dose. 2. Some trials had considerable bias by not including a sufficient number of samples or a broad enough geographical, economic, and age diversity. 3. Timing of vaccine trials in relation to overall prevalence through the COVID-19 pandemic impacts direct comparison. 4. The IgG and IgM antibodies in serum levels had a wide range of variation across the different vaccines after the first or second dose, thus, these data were not included in the metaanalysis. 5. The lack of data on specific categories of patients such as pregnant patients and lifestyles. 6. All RCTs followed up the vaccine and placebogroups one month after both first and second doses, therefore, all reports are related to short-term impacts of the vaccine. 7. For the prevention of database bias, we searched various databases and websites for finding all relevant and gray publications and a proper test for publication bias using Egger’s regression test conducted. We did not find remarkable publication bias in this study by Egger’s regression test. However, publication bias and heterogeneity for some of the pooled results, as well as all the above limitations, must be considered when interpreting the outcomes. 5. Conclusions The adenovirus-vectored and mRNA-based vaccines for COVID-19 showed the highest efficacy after first and second doses, respectively. The mRNA-based vaccines had higher side effects. Only a rare few recipients have experienced extreme adverse effects and all stimulated robust immune responses. All RCTs followed up the vaccine and placebo groups after one month after both first and second doses, therefore, all reports are related to short-term impacts. Due to the timeline, all the vaccines are missing longer-term assessments. This meta-analysis allows us to incorporate relevant new evidence for summarizing and analyzing the clinical features of current vaccines for COVID-19 in phase I, II, and III RCTs. The results support the overall efficacy and safety of all available COVID-19 vaccines, providing clear data-driven evidence to support the ongoing global public health effort to vaccinate the entire population. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/vaccines9050467/s1, Figure S1. Meta-analysis A. Forest plot, B. Funnel plot for the injection site pain as a side effect of different COVID 19 vaccine in phase 2/3 RCT, Figure S2. Meta-analysis A. Forest plot, B. Funnel plot for the injection site pain as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S3. Meta-analysis A. Forest plot, B. Funnel plot for the Swelling as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S4. Meta-analysis A. Forest plot, B. Funnel plot for the Redness as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S5. Meta-analysis A. Forest plot, B. Funnel plot for the Itch as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S6. Meta-analysis A. Forest plot, B. Funnel plot for the Cough as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S7. Meta-analysis A. Forest Vaccines 2021, 9, 467 18 of 21 plot, B. Funnel plot for the Fever as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S8. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S9. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 2 RCT, Figure S10. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 3 RCT, Figure S11. Meta-analysis A. Forest plot,

  1. Funnel plot for the Fatigue as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure

S12. Meta-analysis A. Forest plot, B. Funnel plot for the Fatigue as a side effect of different COVID 19 vaccine in both mRNA-based vaccine, in RCT 2/3, and 3, Figure S13. Meta-analysis A. Forest plot, B. Funnel plot for the Induration as a side effect of different COVID 19 vaccine in RCT 1 2 , Figure S14. Meta-analysis A. Forest plot, B. Funnel plot for the Vomiting as a side effect of different COVID 19 vaccine in RCT 1 2 , Figure S15. Meta-analysis A. Forest plot, B. Funnel plot for the Vomiting as a side effect of different COVID 19 vaccine in both mRNA-based vaccine, in RCT 2/3, and 3, Figure S16. Meta-analysis A. Forest plot, B. Funnel plot for the Diarrhea as a side effect of different COVID 19 vaccine in RCT 1 2 , Figure S17. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect of different COVID 19 vaccine in RCT 1 2 , Figure S18. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect of different COVID 19 vaccine in RCT 3, Figure S19. Meta-analysis

  1. Forest plot, B. Funnel plot for the Arthralgia as a side effect of different COVID 19 vaccine in RCT

2/3, Figure S20. Meta-analysis A. Forest plot, B. Funnel plot for the Chills as a side effect of different COVID 19 vaccine in RCT 2/3, Figure S21. Meta-analysis A. Forest plot, B. Funnel plot for the Pruritus as a side effect of different COVID 19 vaccine in RCT 2/3, Figure S22. Meta-analysis A. Forest plot, B. Funnel plot for the Fatigue as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S23. Meta-analysis A. Forest plot, B. Funnel plot for the Diarrhea as a side effect based on the adjuvanttype in phase 2/3 RCT, Figure S24. Meta-analysis A. Forest plot, B. Funnel plot for the Injection site pain as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S25. Meta-analysis A. Forest plot, B. Funnel plot for the Itch as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S26. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S27. Meta-analysis A. Forest plot, B. Funnel plot for the Swelling as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S28. Meta-analysis A. Forest plot, B. Funnel plot for the Redness as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S29. Meta-analysis A. Forest plot, B. Funnel plot for the Vomiting as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S30. Meta-analysis A. Forest plot, B. Funnel plot for the Fever as a side effect based on the adjuvant type in phase 2/3 RCT, Table S1. Search strategy, Table S2. Quality assessment of included studies. Author Contributions: Conceived and designed the study: A.P., S.G. and M.Z.; Comprehensive research: S.G., M.H.R. and A.P.; Analyzed the data: A.P. and R.J.T.; Wrote and revised the paper: A.P., M.Z., S.G., M.M., M.H.R., D.L.T. and R.J.T.; Participated in data analysis and manuscript editing: A.P., M.Z., S.G., M.M., M.H.R. and R.J.T. All authors have read and agreed to the published version of the manuscript. Funding: The author(s) received no specific funding for this work. Institutional Review Board Statement: The manuscript is a systematic review, so ethical approval was not required for the study. Informed Consent Statement: Not applicable. Data Availability Statement: All data needed to evaluate the conclusions in the paper are included and/or available within the Supplementary Materials. Additional data related to this paper may be requested from the authors. Acknowledgments: None. Conflicts of Interest: The authors declare no competing interest. The author(s) declare no competing financial interests. Vaccines 2021, 9, 467 19 of 21 Abbreviations PRISMA The Preferred Reporting Items for Systematic Reviews and Meta- Analyses Statement MeSH Medical subject headings WHO World Health Organization CDC Center for Disease Control RCT Randomized clinical trial COVID-19 Coronavirus disease 2019 alum Potassium aluminum sulfate VLPs Virus-like particles ORs Odds ratios 6-HB six-helical bundle SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 95% CI 95% confidence interval GMT Geometric mean titer RBD Receptor-binding domain PLpro Papain-like proteases 3CLpro Cysteine-like protease NAb Neutralizing antibody Pro-subunit Protein subunit VLP Virus-like particle BMI Body mass index CFR Case fatality ratio RNA Ribonucleic acid messenger RNA mRNA S-protein Spike protein ACE2 Angiotensin-converting enzyme 2 nsp Non-structural proteins IM Intramuscular References 1. V’kovski, P.; Kratzel, A.; Steiner, S.; Stalder, H.; Thiel, V. Coronavirus biology and replication: Implications for SARS-CoV-2. 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