Vaccines against COVID-19 – Catching the Rays of Hope

COVID-19 pandemic has affected the world in all its dimensions. With herd immunity being a distant and non-practical possibility, vaccination remains most tractable approach to reduce morbidity and mortality. Several early phase clinical trials have proved the immunogenicity of vaccines. The efficacy trials have shown reduction in chance of acquiring COVID-19 disease after vaccination. The vaccines approved for emergency use have reported efficacy above 50% thus making them important public health tool in controlling the pandemic. Nevertheless, several questions remain elusive such as whether these approved vaccines are effective against newer variants of the virus; whether vaccination prevents transmission of the virus in the community; clinical impact of vaccination on morbidity and mortality. This review aims to elucidate the status of vaccine candidates in advanced trials along with the vaccines, which have been granted emergency approvals. Further, we collate the data on vaccines efficacy phase 3 trials and their probability of efficacy against newer variants. Review Article Srinivasamurthy and Bairy; JPRI, 33(47A): 469-488, 2021; Article no.JPRI.75109 470


INTRODUCTION
Coronavirus disease 2019 (COVID-19) pandemic that has practically paralyzed the whole world in terms of economy, education and people movement has seen second and third waves in different regions of the globe. The total global cases involving 221 countries and territories have crossed 227,923,887; with more than 4,686,061deaths [1]. Although many existing drugs have been repurposed, none of them is proved to be effective in preventing COVID-19 [2]. At this stage, the crucial strategy to control pandemic is by vaccination and infection control measure such as physical distancing. The development of safe and effective vaccine for COVID-19 has been on war footing since the advent of pandemic. Various challenges have been overcome for accelerating the process of vaccine development. Many vaccine candidates have been granted emergency use authorization in several countries, while many more are in clinical trials and preclinical phases. Thus, pandemic has overburdened not just public health systems of countries but also the clinical development process.
Nearly 21 candidate vaccines are in public use under emergency use authorization (EAU) and 107 in various phases of clinical trials [3]. As per World Health Organisation (WHO) landscape of COVID-19 candidate vaccines 117 are in clinical development and 194 are in preclinical development [4]. The vaccine platforms being evaluated are by conventional approaches such as protein/adjuvant, inactivated and live attenuated vaccines; and novel approaches such as viral vectors, DNA, mRNA vaccines [5]. The United States Food and Drug Administration (US FDA) has put forward that essential efficacy of at least 50 % for any COVID-19 vaccine candidate for emergency approval [6] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural proteins, which can be targeted for generating neutralizing antibodies, have been characterized by Lee et al. [7] ( Fig. 1) The antigenic receptor-binding domain (RBD) within the spike protein is considered as the prime target of most of neutralizing antibodies [8]. However, emerging evidence suggests other regions on spike protein targetable by novel monoclonal antibodies for better efficacy. The SARS-CoV-2 spike protein and that of severe acute respiratory syndrome associated corona virus (SARS-CoV) of 2003 have reported to be having 75.5% homology, with several novel epitopes [8]. The antibodies against SARS-CoV spike protein is shown to be not beneficial against SARS-CoV-2 spike protein due to these variations [8,9]. The conventional approach used hitherto would have taken longer duration for development of vaccines. However, novel approaches such as mRNA platform have the advantages of fastening clinical development and was employed by several vaccine candidates. Thus, COVID-19 pandemic has not only paved way for historic fast-track development of vaccines but also brought perspectives for use of novel vaccine platforms (Fig. 2).
We searched databases such as PubMed and Google Scholar, for terms COVID, coronavirus, delta covid variant; vacccine; trials; prevention. The relevant and crucial articles were seelcted for this narrative review.  mRNA Vaccines: mRNA vaccines are a novel vaccine platform to protect against infectious diseases. To trigger an immune response, many vaccines put a weakened or inactivated organism into human bodies. Pfizer vaccine became first completely approved vaccine to be in this platform for any disease [12]. Several countries including USA, UK, Canada, Saudi Arabia, UAE, Switzerland, Qatar, Kuwait, Oman and many other countries have approved the same vaccination. The challenge for its effective implementation is its storage requirements of -80°C and -60°C, where it is stable for up to 6 months. For temporary storage, vaccine can be at 2⁰ C and 8 ⁰ C up to five days. However, recent study show that the shelf life of vaccine is much better than previously thought, enabling the storage at -25°C to -15°C for maximum of 2 weeks [13].

VACCINE PLATFORMS AND THEIR CANDIDATES IN CLINICAL TRIALS
National Institute of Allergy and Infectious Disease (NIAID) (USA) is also conducting phase 3 trial of NCT04470427 and is being approved for vaccination by many countries such as USA, European countries. Another mRNA vaccine is developed by Cure Vac, Germany and currently in phase 3 trial. People's Liberation Army, China is aslo developing the vaccine, which is undergoing phase I trial ChiCTR2000034112 [11].
Self-amplyfying RNA (saRNA) vaccines are another next generation RNA vaccine platform capable of self-replication with the help of replicase, inserted in the synthetic RNA transcript itself [14]. The saRNA vaccines would be more effective in triggering immune response, even at lower doses [15]. Imperial College London/ VacEquity Global Health, United Kingdom is developing self-amplyfying RNA (saRNA) vaccine which is undergoing phase I/2 trials. Similarly, Arcturus, Singapore NCT04480957 vaccine which is in phase I trial.
Sinopharm: First approved for emergency use in China for age group of 18-59 years. The vaccine has to be stored at 2-8 degrees centigrade. It is administered on day 0 and booster dose on day 21. It is shown to be having 95-100 % seroconversion. The adverse effects reported are fever, nausea and local reactions [19].
Sinovac: First approved for emergency use in China for the age group of 18-59 years. The vaccine needs to be stored at 2-8 degrees centigrade. First dose is given on day 0 and booster dose on day 28. The seroconversion rate is 97-100%. Mild local effects are seen in few patients [20].

Covaxin:
The complete virus inactivated vaccine developed by Bharat biotech (India) has received emergency use authorization under clinical trial mode. The immunogenicity and safety data were acceptable [21,22].  [39,40]. Local reactions, fever, fatigue etc. are reported as common adverse effects. The mRNA-1273 also showed good titers of binding and neutralising antibodies even at 90 days after the second dose of vaccine [41].

ZyCoV-D (ZydusCadila):
ZyCoV-D is the world's first DNA based vaccine approved for humans [43]. The intradermal vaccine is showed to provide 67% protection against symptomatic COVID-19 and 100% against moderate disease among subjects aged 12 and above [43]. The vaccine is approved under EUA in India based on clinical trial conducted during second wave of COVID-19 of 2021. The phase 1 study has proved tolerability and immunogenicity when 3 doses are administered at 28 days intervals (days 0, 28, 56) [44]. The trial included both needle based administration and needle free injection by PharmajetTropis®. The reported adverse events included tenderness at injection site, joint pain, and fever. 44 The neutralisation antibody titres based on live virus assay showed that 50% and 80% of subjects showed antibodies at day 84 after receiving 2mg needle based and 2mg needleless administration respectively [44].

EpiVacCorona:
Peptide based vaccine EpiVacCorona is approved in Russia. The vaccine is claimed to be immunologically effective in 100% of participants. EpiVacCorona is developed by Vektor State Research Center of Virology and Biotechnology. It consists of SARS CoV2 antigen conjugated with protein carrier with aluminium adjuvant given as two doses with 21 day interval [45]. The vaccine has reported no major safety concerns.17 Turkmenistan has given complete authorization for its use [46].

ZF2001 (Anhui ZhifeiLongcom):
Is protein subunit based vaccine developed by Anhui ZhifeiLongcom. The phase1/2 data suggest tolerability and immunogenicity [47]. The seroconversion rate of neutralizing antibodies after 14 days of third dose is 93-97%. 47 The vaccine is reported to be 81.7% efficacious against alpha variant disease and 77.5% against disease caused by delta variant in a phase 3 study [48,49]. It is given as three doses schedule (day 0, 30, and 60) and found to be retaining neutralizing activity against delta variant of SARS CoV2 [50].

CIGB-66 (CIGB):
Center for Genetic Engineering and Biotechnology (CIGB), Cuba has developed protein subunit based vaccine CIGB-66 also known as Abdala. CIGB-66 is approved under emergency use in Cuba and Venezuela [51]. The phase 1/2 clinical trial indicated a good tolerability and immunogenicity and results of phase 3 study is awaited [52]. It is given intramuscularly at day 0, 14 and 28.

MVC-COV1901 (Medigen):
it is a protein subunit vaccine containing S-2P antigen adjuvanted with aluminium hydroxide and CpG1018 jointly developed by Medigen and Dynavax. The vaccine has obtained emergency use approval in Taiwan [53]. MVC-COV1901 is given intramuscularly at day 0 and 28 has shown tolerability and immunogenicity in phase1 and phase 2 studies with seroconversion rate of 99.8% after 28 days of second dose [54,55].

Pfizer-BioNTech
BNT 162b2 evaluated in multinational placebo controlled observer blinded pivotal efficacy trial (NCT04368728) [58].  [58]. Incidence rate ratio (IRR) is ratio of confirmed COVID-19 per 1000 person-years of follow up in vaccine group to respective illness rate in placebo group [58]. The BNT 162b2 has also shown efficacy in mass-vaccination setting in a large population of 596,618 participants in each group [59]. The vaccine effectiveness was calculated as one minus the risk ratio, using the Kaplan-Meier estimator (

Moderna
Lipid nanoparticle encapsulated mRNA-1273 vaccine is designed to encode fll length spike protein once injected into the body. The phase 3 randomised observer blinded placebo controlled trial involving vaccine and placebo arms with 15210 participants in each has been conducted during July 27, 2020 to October 23, 2020 [60].

AstraZeneca/Oxford
ChAdOx1 nCoV-19 vaccine (AZD1222) has been studied in four phase 3 blinded, randomised controlled trials at Brazil, South Africa and UK. The interim analysis of these pooled data is published [61]. ChAdOx1 nCoV-19 is studied in two standard doses (SD) (5X 10 10 viral particles each) in SD/SD cohort, a subset of participants in UK were recruited for half dose as first dose (low dose LD) and standard dose as second dose in LD/SD cohort. Symptomatic COVID-19 confirmed by nucleic acid amplification test (NAAT) swab test 14 days after second dose was considered as primary efficacy endpoint. The data of period of nearly 6 months (April 23 rd to Nov 4 th 2020) showed enrollment of 23848 participants. In SD/SD cohort, 27 of 4440 participant (0.6%) in ChAdOx1 nCoV-19 vaccine group and 71 of 4455 (1.6%) in control group developed the primary efficacy end point. The vaccines efficacy calculated as 1-relative risk from Poisson regression model adjusted for age was showed to be 62.1% (Table 3).
Among LD/SD cohort there were three of 1367 (0.2%) in vaccine group vs 30 of 1374 (2.2%) in control group met the primary efficacy end point. The vaccine efficacy was calculated to be 90.0%. The overall vaccine efficacy was calculated to be 70.4% (95% CI, 54.8-80.6%). The safety analysis during the median follow up of 3.4 months there were 84 events in vaccine group and 91 in control group. Voysey et al. also showed that vaccine efficacy was higher in participants who had more than six weeks between the two does (65.4%) than among participants who had second dose in less than six weeks (53.4%) [61].
The recent study showed the efficacy of single dose vaccines of both BNT162b2 or ChAdOx1 COVID-19 in causing significant reduction of symptomatic cases and severe COVID-19 infection in elderly participants [62].

Sputnik V
Heterologous recombinant adenovirus (rAd)based vaccine, Gam-COVID-Vac (Sputnik V) had showed 91.6% efficacy as per interim analysis of phase 3 trial [63]. The study involved 19866 participants included for primary outcome analysis. From the day of 2nd dose of vaccine (21st day) 0.1% of 14964 participants of vaccine group and 1.3% of 4902 in placebo group were found to be COVID-19 positive, with vaccine efficacy of 91.6% [63] (Table 3). Among a total of 21977 participants, 16501 were in vaccine group and 5476 were in placebo group and were considered for safety analysis. Commonly reported adverse events were grade 1. Serious adverse events (SAEs) reported were, 0.3% of vaccine group and 0.4% of placebo group and none were considered related to vaccination. There were three deaths in vaccine group and one death in placebo group and were considered not related to vaccination. Vaccine efficacy is 1-odds ratio expressed as percentage; a is number of participants meeting primary endpoint in vaccine group; b is total number of participants in vaccine group; c and d are respectively participants meeting primary endpoint and total number of participants in placebo group; odds ratio is ad/bc; NAAT nucleic acid amplification test; SD -standard dose; LD -low dose

CoronaVac (Sinovac):
The inactivated vaccine has shown to have overall efficacy of 50.65 and, 83.70% in preventing medical treatment, and 100% for prevention of hospitalization, severe, and fatal disease [64,65]. The vaccine has received conditional marketing authorization in China [64].

Sinopharm:
The phase 3 efficacy data is yet to be published by the sponsors. However the efficacy data released to the public domain show 79.34% in multinational study [66]. The data available in public domain also indicate that the vaccine is 100% effective in preventing moderate and severe disease [67].

Johnson and Johnson Vaccine:
Ad26.CoV2.S of Janssen Pharmaceuticals (Johnson and Johnson) when given as single injection has showed overall efficacy of 66% [68]. The promising results are the vaccine also showed 57% efficacy in South Africa where B.1.351 is becoming a dominant variant. The study also demonstrated 100% prevention of hospitalization. Further, asymptomatic infection was also prevented with an efficacy of 88%. The common adverse reactions included headache, fatigue, muscle aches, nausea and fever.
Cansino: vector based vaccine developed as a single dose shot. The vaccine was approved for emergency use among military in China last year, and later by Mexico [69,70]. The vaccine efficacy is claimed to be of 65.7% [70].

Covaxin:
The Bharat biotech has released the phase 3 efficacy data of their inactivated vaccine [22]. The phase 3 study involved 25,800 participants aged between 18-98 years of age.
The primary endpoint being RT-PCR-confirmed symptomatic COVID-19 occurring at least 14 days after the 2 nd dose. First interim released to public domain show that 36 cases of COVID-19 were found in the placebo group as compared to 7 cases in vaccine group. The reported vaccine efficacy is 80.6%. the safety data were found to be similarly distributed between the groups [22].

EFFICACY DATA OF VACCINES IN PROCESS OF APPLYING FOR EUA AS PUBLISHED ON COMPANY WEBSITES
NVX-CoV2373, from Novavax demonstrated in phase 3 UK trial: 89.3% overall efficacy (95.6% against the original strain). In another phase 2b South Africa trial the vaccine showed 60% efficacy against new variant virus [71,72]. The vaccine is well tolerated and showed good immunogenicity as compared to human convalescent sera in phase1/2 clinical trials.

COVID-19 VARIANTS AS CHALLENGES TO VACCINES BEING DEVELOPED
Though RNA viruses are known to have higher mutation rates than DNA viruses, coronaviruses are show lesser mutation rates due to correction of errors by specific enzymes [73]. However, high rate of mutations are reported in a proteogenomic analysis from COVID-19 patients [74]. A mutation indicate change in the sequence, as in D614G where aspartic acid to glycine substitution at 614 position of spike protein.
Whereas, a variant is change in sequence of genome, which expresses phenotypic differences such as in antigenicity, transmissibility and virulence. D614G variants have been the predominant variant globally since June 2020.

SARS-CoV-2 VOC 202012/01 (Variant of
Concern, year 2020, month 12, variant 01) also known as 20I/501Y.V1 or B.1.1.7 was detected in United Kingdom authorities. The variant is shown to be more transmissible with no effect on length of hospitalization and case fatality. B.1.1.7 variants are shown to be 36-71% more transmissible than the native variant [75]. VOC 202012/01 variant consists 23 nucleotide substitutions, of which the deletion at position 69/70del was shown to affect the S gene targeted diagnostic PCR assays. However, globally PCR assays utilize multiple targets and hence variants are not postulated to affect diagnosis. Another variant 501Y.V2, (B.1.351) was detected in South Africa. The variant is characterized by rapid transmissibility (more than 50%) with no evidence on its association with disease adverse outcomes [75].
Both UK and South Africa variants have characteristic N501Y mutations. SARS CoV-2 N501Y is reported to increase the transmissibility in these variants [76]. The mutant has posed a new challenge to vaccine development process.
N501Y mutant S1-RBD binding to STE90-C11 is shown to increase significantly by in-silico Free energy of binding (FEP) and replica exchange solute tempering (REST) method [77]. STE90-C11 is a neutralizing antibody from convalenscent patients produced against COVID-19. STE90-C11 is shown to be effective against several RBD mutations as well previously [78].
However several studies have shown loss of neutralization ability of human convalescent serum against SARS-CoV-2 variants containing the E484K mutations [81][82][83]. Further, convalescent and BNT162b2 mRNA vaccine immunised sera neutralized SARS-CoV-2 Brazilian (B.1.1.248) variants better than South African variants (B.1.351) even though both variants coded for E484 and N501 mutations. Thus distinct mutations in NTD regions of S protein may also have a role in development of viral resistance [83].

VACCINATION: PROTECTION AGAINST DISEASE OR INFECTION TRANSMISSIBILITY
Whether vaccinated persons spread, the infection is unclear currently. However, COVID-19 human challenge study being conducted in the UK would answer many such questions [84]. SARs-CoV-2 with doubling time of 2.3-3.3 days and R 0 (reproduction number) of 5.7 it is predicted that 82% of the population need to be immune either by vaccination or past infection to stop transmission and develop herd immunity [85]. However with rising cases of clinically significant variants achieving herd immunity is a distant possibility. Rising cases of SARs CoV-2 variants, also pose threat to vaccine effectiveness.
Nevertheless, the data showing that vaccines prevent severe COVID-19 disease itself is the hope to begin "living" of global population, which was standstill due to pandemic [86] As indicated by the WHO, in spite of the available vaccines most effective stake to reduce the burden of infection still exists with social behavior of physical distancing and masks [86]. The data platform statistica had predicted that 50% reduction in number of new infections caused by a patient would translate to 27 fold reduction of number of infected after 1 month, which may be achieved by social behavioral changes [87].

VACCINATION CHALLENGES AND WAY AHEAD
With the world, witnessing the real time, fastest development of vaccines for a pandemic there are also several inadequacies so far and challenges ahead. Most of the countries showing lower vaccine coverage due to hindrances and voluminous task of vaccinating the populations worldwide [88]. The differences in regulatory status of vaccines among countries have adversely affected the international travelling during pandemic [89]. This has only resulted to add more to vaccine hesitancy and vaccine inequality due to injustice situation where vaccine of one country is not recognized by other country. Further, COVID-19 vaccine development is also characterized by commercial race, underreporting of data and mass preordering instead of global collaboration [90]. Hence, global harmonization among countries in vaccine development, data reporting, production and distribution, along with suppressing of socialpolitical, commercial interests are essential for equitable access of global vaccines which are safe and effective [90,91]. There is also need for harmonized surveillance and communication among countries for achieving herd immunity [90].
The global efforts led by WHO gave rise to COVAX, for ensuring equitable distribution of vaccines globally [92]. The WHO in collaboration with the Global Vaccine Alliance (GAVI), and the Coalition for Epidemic Preparedness Innovations (CEPI) has committed distribution of 2 billion doses by the December of 2021. COVAX initiative is aptly based on the motto "no one is safe unless everyone is safe" thus emphasing the concept of one safe world.

CONCLUSION
As reported, many pharmaceutical companies are involved in vaccine development for the prevention of COVID-19. Many of them have been approved for emergency use in various countries around the globe and several are in various phases of clinical trials. Of late, the new mutated form covid-19 is reported in many parts of the globe and posing new threat. The ray of hope is that the vaccines are effective in preventing severe disease. Further, the vaccines in pipeline are being studied against these mutated forms and would see the light in coming days. However, one has to exercise social restraint in the form of physical distancing and masking until that time.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.