An assessment of the strategy and status of COVID-19 vaccination in India

The COVID-19 disease continues to cause devastation for almost 3 years of its identification. India is one of the leading countries to set clinical trials, production, and administration of COVID-19 vaccination. Recent COVID-19 vaccine tracker record suggests that 12 vaccines are approved in India, including protein subunit, RNA/DNA, non-replicating viral vector, and inactivated vaccine. Along with that 16 more vaccines are undergoing clinical trials to counter COVID-19. The availability of different vaccines gives alternate and broad perspectives to fight against viral immune resistance and, thus, viruses escaping the immune system by mutations. Using the recently published literature on the Indian vaccine and clinical trial sites, we have reviewed the development, clinical evaluation, and registration of vaccines trial used in India against COVID-19. Moreover, we have also summarized the status of all approved vaccines in India, their associated registered clinical trials, manufacturing, efficacy, and their related safety and immunogenicity profile.


Introduction
The sudden emergence of SARS-CoV-2 and its newly emerging variant has swept the world. Scientists worldwide have been working hard to understand and fight this disease. The only preventive measures are wearing masks, maintaining social distancing, self-isolation, and, most importantly, vaccination. Mass vaccination is the most effective and decisive option to prevent COVID-19. After sequencing the genome in January 2020, scientists set themselves at the compulsory production of vaccines in a short time. However, with the emergence of new mutant strains of the SARS-CoV2 variants, there was an urgency for a concrete and effective plan. World Health Organization (WHO) declared a severe respiratory disorder syndrome that originated in Wuhan city, China, as a global public health emergency on January 30, 2020, and named the disease COVID-19 on February 11, 2020 [1][2][3]. On March 11, 2020, WHO declared it a global pandemic [4,5]. India reported the first confirmed case in Kerala on January 27, 2020 [6]. The spread of COVID-19 was relentless spreading in almost all over the countries, leading to severe public health and social and economic upheaval. A detailed study on novel coronavirus led to a mutual understanding that a COVID-19 vaccine is likely the most effective approach to sustainably controlling the COVID-19 pandemic globally [7]. Operation Warp Speed (OWS) USA was initiated, which cooperates with the National Institute of Health (NIH), Centers for Disease Control and Prevention (CDC), and other organizations to develop strategies for vaccine development, production, and distribution of large quantities of vaccines (https:// www. cdc. gov/ washi ngton/ testi mony/ 2020/ t2020 0702. htm). With a massive surge in COVID-19 disease infections and deaths during the second wave of infection, India needed to take Sneh Lata Gupta and Surbhi Goswami shared first author.  [9,10]. After the successful preclinical studies, Bharat Biotech commenced the clinical trials of Covaxin in the country in July [11].
Covaxin is based on the SARS-CoV2 Spike protein. Neutralizing antibodies are produced against Spike protein and their components such as RBD and NTD upon vaccination [12]. The SARS-CoV2 virus was cultured and propagated at NIV. Beta-propiolactone was used for the inactivation of these viral cultures, which inactivates the whole virion while the spike protein remains intact to the virus [13][14][15]. The inactivated virus was then combined with a small quantity of an adjuvant toll-like receptor 7/8 agonist with an aluminum-based chemical alum (Algel-IMDG) that stimulates the immune system to boost its response to vaccination [16,17] (Fig. 2). Phase 3 clinical trial (NCT04641481) in India (CTRI/2020/11/028976) showed BBV152 vaccine efficacy was approximately 77.8% 2 weeks post-second dose without any major side effects and anaphylaxis [18]. This efficacy was higher in severe COVID cases at 93.4%, whereas in asymptomatic cases, efficacy was 63.6% [9]. WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommended an interim policy for COVAXIN usage. Per their recommendation, this vaccine was safe for adults above 18 years old, including pregnant women, breastfeeding and non-breast-feeding women, old age people, health care workers, and immunocompromised persons. This vaccine should not administer to children and persons who are suffering from anaphylaxis, fever, or acute COVID infection. Despite distributing the vaccine in 23 other countries, it is mostly used in India. It is given in two doses (0.5 mL each) via the intramuscular route in 4 weeks intervals. A booster dose can be taken after 4-to 6-month intervals, especially in older and immunocompromised people. SAGE also suggested taking a second dose of either mRNA vaccine (Pfizer or Moderna) or adenovirus vector-based vaccines such as Covishield or Vaxzevria followed by the first dose of COVAXIN. This combination either provides equivalent or better immunogenic responses (https:// www. who. int/ news-room/ featu re-stori es/ detail/ the-bharat-biote ch-bbv152-covax in-vacci neagain st-covid-19-what-you-need-to-know). Administration of Covaxin results in the activation of both B cells and T cells which results in.antibody production and T cell cytotoxic activity. B and T cells also form memory B cells, which respond upon natural SARS-CoV2 infection, thus subsequent rechallenge [8,[19][20][21]. Antibodies prevent the virus from entering lung cells by targeting the spike protein.
The durability of BBV152 vaccine-mediated antibody response declines after 6 months of their initial two doses regimen [22,23]. Phase 2 trial (NCT04471519) showed improvement in neutralization titers as measured by PRNT50 (plaque reduction neutralization test) and seroconversion rate after BBV152 booster after 6 months of the first series of vaccination. Booster-dose-vaccinated individuals also showed better protection against various circulating variants of concern, such as Alpha, Beta, Delta, and Delta plus [24,25]. This shows antibody cross-reactivity to spike variants. They also found an enhanced B and T cell memory population without any severe side effects [26]. COVAXIN has also been shown to  [27]. The major vaccine response was found to be Th1 (T helper cell 1) with IgG1/IgG4 ratios above 1, without any serious adverse side effects or deaths [28].

Covishield
The University of Oxford partnered with AstraZeneca to generate a coronavirus vaccine called ChAdOx1 nCoV-19 or AZD1222 [29]. In February 2020, SII began testing vaccine candidates on animals. The institute also announced the application for the conduction of clinical trials in April 2020 from the Drug Controller General of India (DCGI) [30]. SARS-CoV2 spike protein is cloned into Adenovirus viral vector backbone in this vaccine. For vaccine preparation, ChAdOx1, a modified form of chimpanzee adenovirus, is used [31]. The Adenovirus activates the immune system by releasing DAMPs (damageassociated molecular patterns) and activating the anti-viral state in neighboring immune cells [32,33] (Fig. 3). The Oxford-AstraZeneca vaccine causes the immune system to react more forcefully to the spike proteins by raising this alert. The antibodies get themselves attached to coronavirus spikes, killing the virus and further helping to prevent infection as it blocks the spikes from attaching to other healthy cells, as reported in a phase III clinical trial study (ISRCTN89951424). Pooled analysis of clinical trials for Covishield (ISRCTN89951424, NCT04324606, NCT04400838, and NCT04444674) confirmed the vaccine efficacy of 76% after a single dose of vaccination. Efficacy was found to be 81.3% in participants receiving two standard doses with a longer prime-boost interval than those with a short interval (efficacy 55.1%) [34,35]. SAGE also recommended an interim policy for recombinant ChAdOx1 vector-based vaccine trade names such as Vaxzevria and COVISHIELD [36]. The vaccine efficacy of these vaccines is 72% (95% CI: 63-79%) for asymptomatic infected patients and 85% (95% CI: 58-94%) for old age people. Vaccines are given in two doses (0.5 mL) in a 4-to 12-week interval via the intramuscular route. Longer intervals gave improved immune responses [37]. Regarding mix and match, vaccine combination showed that ChAdOx1 vector-based vaccine followed by mRNA vaccines (Pfizer or Moderna) generate enhanced neutralizing antibody and T cell responses [38]. As per WHO recommendations, if people suffer from anaphylaxis reaction, allergic reaction, acute fever, and thrombosis with thrombocytopenia syndrome (TTS) after the first dose of this vaccine, they should be prohibited from subsequent doses. People suffering from underlying conditions or comorbidities such as respiratory illness, HIV, diabetes,  etc., and immunocompromised persons at risk of getting COVID-19 should get the vaccination, which has been shown to be safe and effective. The vaccine is also effective in pregnant and breastfeeding women [36].

Sputnik V
Ministry of Health, Russia, undertaking body "Gamaleya Research Institute" developed a vaccine for coronavirus and named it Sputnik V or Gam Covid Vac which collaborated with Dr. Reddy's Laboratories, Hyderabad, India [39,40]. Spike protein gene is cloned in two kinds of adenovirus Ad26 and Ad5 backbone. Adenovirus vectors serve as a carrier to deliver. The use of two serotypes intends to eliminate any previous Sputnik demonstrated 97.6% efficacy without any strong adverse effects in vaccinated persons in Russia [41]. Indian pharmaceutical giant Dr. Reddy made a deal with phase 2/3 human trials in India of Russia's Sputnik V vaccine and produced 100 million doses [42]. The study suggests that both Sputnik V and Sputnik Light are effective against SARS-CoV2 delta variant [43,44].

ZyCoV-D
ZyCoV-D was developed by Zydus Cadila and supported by DBT-BIRAC. It received emergency use authorization in August 2021 for children and adults 12 years and above [45]. It is a plasmid DNA-based COVID vaccine that is administered intradermally through a PharmaJet needle free applicator. Phase 1/2 study showed that ZycoV-D was able to elicit a good immune response with no safety concerns [46]. Interim results from the phase 3 trial ZycoV-D showed an efficacy of 66.6% with adverse effects similar to placebo upon administration of three doses of intradermal needle-free vaccination [47].

Corbevax (BECOV2A)
Corbevax manufactured by Biological E limited is based on the RBD subunit which interacts with human host cell ACE2 (angiotensin converting enzyme) receptor. Safety, immunogenicity, and reactogenicity of Corbevax were assessed in phase 1/2 clinical study as CTRI/2021/06/034014 and CTRI/2020/11/029032. Low or no incidence of adverse events was observed after receiving two doses scheduled in 28-day intervals. CpG1018 and aluminum hydroxide were used as adjuvants in this vaccine formulation which showed higher anti RBD-IgG binding and neutralization titers and improved cellular response [50,51]. Corbevax has been shown to be immunologically superior and safer compared to Covishield in the larger and relatively aged populations [52].

GEMCOVAC.™-19
It is an indigenously developed mRNA vaccine in India developed primarily by Genova Biopharmaceutical limited which is part of Emcure Biopharmaceutical Limited, headquarters situated in Pune, India. It received emergency use authorization for adults on June 22, 2022, from Drugs Controller General. Phase 2 and 3 studies (CTRI/2022/04/041880) found that the vaccine showed less or no incidence of adverse side effects (www. ctri. nic. in).

Spikevax (MOD)
Spikevax, previously known as Moderna COVID-19 vaccine, is an mRNA-based vaccine developed by Moderna. The active substance of the vaccine is CX-024414, which is an mRNA encoding SARS-CoV2 spike protein. It was approved by FDA on January 31, 2022, for individuals 18 years of age and over (https:// spike vax. com/). NCT04470427 phase III clinical trial suggests that its vaccine efficacy was more than 90% and it is safe to use. It is a lipid nanoparticle-encapsulated mRNA vaccine [53]. The vaccine is administered as a series of two doses, 1 month apart.

Sputnik Light
This vaccine is a recombinant adenovirus type 26 (rAd26)based vector containing the SARS-CoV2 spike gene. It is administered as a single dose. Phase 1 clinical trial results showed that there were mild or moderate symptoms postinjection with no severe adverse events observed in all participants. Both seropositive and seronegative participants showed strong humoral (enhanced neutralizing antibody response) and cellular immune response (increased antigen-specific T cell proliferation, production of IFNγproducing cells, and their cytokine secretion) upon vaccination [54]. Sputnik Light is also proven to be effective against the Delta variant of coronavirus [43,44].
iNCOVACC An intranasal COVID-19 vaccine also known as BBV154 is manufactured by Bharat Biotech. Clinical trial (NCT04751682) shows the safe and immunogenic potential of this vaccine. This vaccine provided not only neutralizing antibody and T cell proliferation but also mucosal IgA. Thus, it is effective at the site of both infection as well as transmission and protects the upper and lower respiratory tract. It is targeted at the nasal mucosa site. It is the world's first intranasal vaccine that got the first restricted use authorization approval in India for adults. It is based on an adenovirus-based vector and stable at 2-8 °C temperature [55,56]. On September 22, 2020, Codagenix, Inc. announced the production of CDX-005, an intranasal, live-attenuated vaccine by the Serum Institute of India. It is funded by investors such as Adjuvant Capital and Topspin partners. The preclinical studies yielded positive safety and efficacy results for the vaccine [57]. Nasal vaccines are given as booster shots.

Jcovden
Previously known as COVID-19 vaccine Janssen. This vaccine is based on an adenovirus vector (recombinant Ad26.COV2-S). The clinical trials showed its vaccine efficacy was 67%. This vaccine is primarily manufactured by Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson. It is administered as a single dose [58].

Vaxzevria
Vaxzevria (ChAdOx1 nCov19) is a chimpanzee adenovirus (ChAd)-based COVID-19 vaccine developed by AstraZeneca and is quite effective against Delta variant. The vaccine is approved by EMA for people aged 18 years or older. It is given in two doses with the second dose 4 to 12 weeks after the first dose [59]. The results from a 90-patient study demonstrated that antibody levels were elevated in those with a longer interval between second and the third dose [60].

Mixed inoculation of vaccine in India
Heterologous prime-boost vaccine delivery is based on the administration of SARS-CoV2 spike antigen. This is an important aspect as it leads not only to improved protective efficacy in terms of durable and stronger immune response but also to optimize the usage of available vaccines at that time in developing countries like India compared to homologous vaccine regimens. Usage of adenovirus-based vaccines such as Sputnik or Covishield followed by mRNA-based (Pfizer or Moderna) or proteinbased (Novavax) reduces the chance of adverse immune response against the adenovirus-based vector [61]. The example includes the primary vaccine from Covishield, and then a booster with Corbevax showed better B cell and T cell immune response [62]. Another recent report tested Covishield and Covaxin in a homologous and heterologous booster in all possible combinations and showed that Covishield boost followed by Covaxin primary series of combinations shows an improved immune response compared to all other possible combinations [63].

Indian government drive in the development of COVID-19 vaccine
The Indian government announced a $120 million grant for COVID-19 vaccine research on November 29, 2020 for Mission COVID Suraksha (Safety) to vaccinate the larger population of India and to accelerate the preclinical and clinical development of different vaccine candidates. The government should have also included a very fundamental objective of producing raw materials for the vaccine candidates. The fund should have encouraged the production of raw materials for the vaccines within the country itself, thus standing completely on the slogan of "Atamanirbhar Bharat" (self-reliant India). So far, a total of 12 vaccine candidates have been supported by the Department of Biotechnology (DBT), India [42,64,65]. After Pfizer's COVID-19 vaccine approval, BioNTech received emergency clearance for the mass distribution of the vaccine in the UK and Bahrain on December 2, 2020, via Emergency Use Authorization (EUA) [66,67]. However, this vaccine needs to be stored at a temperature of -70 °C, which is not sustainable in India and poses the biggest challenge for India. Serum Institute of India (SII) applied for the EUA of the Covishield vaccine on December 7, 2020, during its phase-3 trials, conducted not just across India but also in the UK and Brazil. One of the significant advantages of this vaccine candidate is that it can be easily stored at temperatures between 2 and 8 °C. It got approval from the UK on December 30, 2020 [68]. On January 2, 2021, the Drugs Controller General of India (DCGI) granted the approval to AZD1222, COVID-19 vaccine developed by the Oxford-AstraZeneca, previously called ChAdOx1, a chimpanzee adenovirus vaccine and currently manufactured by Serum Institute of India as COVISHIELD and indigenously developed BBV152 or COVAXIN by Bharat Biotech for restricted emergency use in the country [69][70][71]. January 16, 2021 marked the beginning of a nationwide vaccination drive in India, aimed to immunize 3 billion people, including 0.3 billion healthcare and frontline workers, along with 2.7 billion people above 50 years of age and the under-50 population groups with co-morbidities [42]. India launched a campaign called "Vaccine Maitri,"(Vaccine Friendly), a humanitarian and commercial initiative undertaken by the Indian government to provide COVID-19 vaccines to countries across the globe, with our neighbors Maldives and Bhutan becoming the first recipients [72,73]. The second dose of COVID-19 vaccination started on February 13, 2021 for those recipients who have completed 28 days after getting their 1st dose. Pre-registration facility was provided on Cowin 2.0, and the Arogya Setu app, also on spot registration facility was provided for the beneficiaries [74] (https:// www. aarog yasetu. gov. in/). As per Co-Win (Winning over  website data, in India so far, among all vaccines available; the most widely used vaccine is Covishield followed by Covaxin and then Corbevax, with very few dose administration of another available vaccine such as Sputnik V and Covovax (https:// dashb oard. cowin. gov. in/). To accelerate the process, under Ayushman Bharat PMJAY, 10,000 private hospitals and 600 private hospitals under CGHS (central government health scheme) were used for this phase, 529 government hospitals and 761 private hospitals announced to offer the vaccine which the government hospitals provided free of cost, 250 was the MRP in the private hospitals [75,76]. Thus, Indian government actively participates in preventing COVID-19 disease from India.

Strategies for allocation of COVID-19 vaccines in India
The Indian government announced free COVID-19 vaccination to all citizens on January 16, 2021. However, at the beginning of the epidemic, COVID-19 vaccines were preferentially administered to 30 million healthcare workers, initially having limited resources of manpower and cold chain facilities. Per the National Expert Group on Vaccine Administration for COVID-19 (NEGVAC), committee recommendations gave the priority list of COVID-19 vaccines. It included healthcare workers or frontline workers (~ 3 million) as the first and foremost priority. The second priority in line was given to elderly persons and people with underlying comorbidities, pregnant women, and a large number of medical and paramedical staff. [42,77]. Vaccinating healthcare workers is important as they are at high risk of exposure while treating SARS-CoV-2-infected patients. And further, if they get infected, all other healthcare services will be reduced. An initial report from Wuhan hospital (where the initial outbreak happened) showed that among the first 138 patients infected with SARS-CoV2, 40 (29%) were healthcare workers. [78]. This illustrated the significance of vaccinating healthcare workers as a first preference to control epidemics.

Indian COVID-19 vaccines compared to the rest of the world
In India, Covishield and Covaxin constitute a large portion of vaccines administered. India has contributed significantly to the overall COVID-19 vaccine drives globally. India approved their first nasal iNCOVACC vaccine, similar to China [79]. Comparing efficacy, storage conditions, doses, and cost per dose play an essential role in the distribution and administration of vaccines. [80]. Table 3 shows the comparison of the Indian vaccine to other approved and most-used vaccines globally. It showed that mRNA vaccines (both Pfizer and Moderna) require ultra-low temperature storage (− 15 to -80 °C), so expensive per dose compared to adenovirus-based such as Covishield, or inactivated virus-based such as Covaxin, which require regular 4 °C refrigeration which can be feasible in developing countries [81,82]. In the USA, bivalent mRNA vaccines were also approved for a booster to deal with the Omicron variant, but no such vaccines are available in India so far [83]. Similarly, mRNA vaccines were also approved for children 6 months and above in the USA, but there was limited success in pediatric vaccine availability in India. Covaxin (BB152) was approved for adolescents (12)(13)(14)(15)(16)(17)   relevant in a country like India, which is home to diverse socio-economic and cultural variations. More and more data available in the public domain related to vaccine efficacy, immunogenicity, and safety data will increase reliability in mass-scale vaccination and herd immunity.

Current challenges in vaccine success
COVID-19 is an ongoing pandemic that has resulted in global health concerns, economic burdens, and social life disturbance. The vaccination campaign is the first and foremost successful method to counteract the COVID-19 pandemic. Moreover, sufficient vaccination coverage is conditioned by the people's acceptance of these vaccines. All vaccines reviewed here are based on ancestral SARS-CoV2 (Wuhan strain) spike. However, the newly emerging SARS-CoV2 variant with increased transmissibility and escaping from their neutralization poses a serious concern for achieving herd immunity. Thus, despite vaccine availability, constant efforts are needed to get boosters and development of more effective strategies to design the COVID-19 vaccine.

Conflicts of interest
The authors declare that they have no conflict of interest.
Ethical approval This article does not contain any studies with human participants or animals performed by any authors.