A brief overview of various vaccines against nCOVID19, including safety, efficacy, reported cases, clinical trials, and progress

Abstract

Even if many countries are against it since vaccinations are not readily available, industrialized countries continue to make some vaccines designated under the World Health Organization's emergency use listing mandatory for entry into their countries. The first half of 2021 has seen the introduction of SARS-CoV-2 vaccinations in several countries, after the exceptional speed of vaccine development and testing in 2020. Using keywords in online databases such as Pubmed, Scopus, Web of Science, Cochrane, and Embase, this systematic search was carried out. The findings were collected into a report. We were unable to do an adequate human study because we included so many different kinds of vaccinations. A look at current vaccination-controlled trials and actual facts on immunization success is also presented. The efficacy of new vaccines is continually being tested in ongoing vaccine trials. Increasing the alternatives for global vaccine production to manufacture sufficient vaccine shots for international usage and to enhance the statistics for the potential utility of various vaccination platforms in forthcoming pandemics are also a result of this.

Introduction

Global health, economic, and social crises have been triggered by the new SARS-CoV-2 infection. Wuhan, China, was the first place to record and identify a cluster of pneumonia cases with an unknown origin in December of 2019.[¹] There were millions of fatalities worldwide due to a virus that was referred to as the 2019 novel coronavirus. In January 2020, the World Health Organization (WHO) designated the outbreak a public health emergency of worldwide significance.[²] The WHO proclaimed a coronavirus disease on March 11, 2020, owing to the virus's global expansion and rising virulence.[³] As of January 16, 2021, a total of 3 vaccines have been certified for alternative use for the public, including the newly approved Sputnik-V and the COVAXIN. As of January 16, 2021, India began its COVID-19 immunization campaign. COVAXIN's emergency limited use clearance was questioned owing to a lack of appropriate safety and effectiveness evidence, which led to a loss of trust and faith in indigenously manufactured vaccines. The COVAXIN trials were also heavily scrutinized due to suspicions of unethical trial conduct. It was extensively mocked in the media and by members of the public. 2.8 billion shots of COVID-19 vaccines were administered within 16 months of the first immunization trials. Figure 1 depicted the composition of vaccines and basic structure of SARS-CoV-2.

Figure 1: General components of vaccines and the structure of novel coronavirus

COVAXIN®

Indian biotech company Bharat Biotech and the ICMR-National Institute of Virology (NIV) have produced an indigenous COVID-19 vaccine called COVAXIN®. Viruses that cannot spread disease but even educate the immune system to respond to infection are also included in this category.[⁴] In addition to 6 g of whole-virion inactivated SARS-CoV-2 antigen (Strain: NIV2020-770), COVAXIN also includes additional inactive components such as PO₄³⁻ buffer saline for up to 0.5 ml, 250 g Al (OH)³ gel, 2.5 mg TM 2-C₈H₁₀O₂, and 15 g TLR 7/8 agonist (imidazoquinoline). Multidose vials of the vaccine are available for use at 2°C–6°C and do not need sub-zero storage or reactivation.[⁵]

Working Mechanism

Like CoronaVac (the Chinese vaccine created by Sinovac), the virus that causes SARS has been genetically modified to limit reproduction.[⁶] Taking two doses of COVAXIN 28 days apart is suggested. A vaccination that has been rendered inactive, derived from the SARS-CoV-2 strain, is known as COVAXIN. For a more effective immune response and longer-lasting protection, vaccination adjuvants (such as Alhydroxiquim-II) are added to the vaccine mix. Inactivated virus is combined with the Alhydroxiquim-II adjuvant from Kansas-based ViroVax to create a vaccine nominee.[⁷]

The vaccination has peer-reviewed research data

To determine if the vaccine is safe and effective, COVAXIN has published a Phase I clinical study.[⁸] All of the 375 people who got the vaccination showed a considerable increase in antibody levels. However, a preprint of the Phase II study results has been provided on MedRxiv.[⁹] Preliminary results show an improved immune response and acceptable safety outcomes. Phase III studies have recruited 25,800 people since November. As of the March 3, 2021, interim efficacy data from Bharat Biotech revealed a clinical effectiveness of 81%.[¹⁰]

When was COVAXIN made available to the general public?

India's leading medicine regulator, the Central Drugs and Standards Committee Organisation (CDSCO), approved COVAXIN's alternative authorization on January 3, 2021, while Phase III clinical investigations are still in progress and Phase II data have not yet been reported.[¹¹] Protecting against the UK variant's spread was an issue raised by regulators. Despite encouraging findings in a preprint, no peer-reviewed data exists to support the vaccine's efficacy against this strain.[¹²] Health professionals and individuals over the age of 60 are presently being given the vaccination in India, as well as those with underlying medical conditions.

Recent clinical efficacy

Raches Ella et al. revealed that BBV152, a complete virion inactivated SARS-CoV-2 vaccine combined with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG), was clinically effective against COVID-19 infection in Indian adults. To assess the effectiveness, safety, and immunological lot consistency of BBV152, we conducted a randomised, double-blind, placebo-controlled, multicenter, phase 3 clinical trial in 25 Indian hospitals or medical clinics. A computer-generated randomization scheme (stratified for the presence or absence of chronic conditions) was used to assign adults (age 18) who were healthy or had stable chronic medical conditions (not an immunocompromising condition or requiring treatment with immunosuppressive therapy) to receive two intramuscular doses of the vaccine or a placebo, which were given 4 weeks apart. A masked expert adjudication panel and an unmasked contract research organisation evaluated results; participants, researchers, study coordinators, study-related staff, the sponsor, and nurses who administered the vaccines were all blinded to the treatment group allocation. The main result was whether the BBV152 vaccine was effective in preventing the first instance of laboratory-confirmed (RT-PCR-positive) symptomatic COVID-19 (any severity), occurring at least 14 days after the second dose in the population that adhered to protocol. All trial participants who had received at least one dose of the vaccine or the placebo were evaluated for safety and reactogenicity throughout the length of the experiment. We enrolled 25 798 people between November 16, 2020, and January 7, 2021, randomly assigning 24 419 to receive two doses of BBV152 (n = 12 221) or a placebo (n = 12 198). A minimum of 14 days of follow-up after the second dosage for 16 973 originally seronegative individuals was required for the effectiveness analysis to include 130 cases of symptomatic COVID-19. In all, 24 (0.3% of instances) among 8471 vaccine recipients and 106 (1%) among 8502 placebo recipients resulted in a vaccine effectiveness estimate of 77.8% (95% CI: 65.2-86.4). 3194 participants experienced 5959 adverse events in the safety population (n = 25 753). Adults with COVID-19 symptoms and test confirmation responded very favourably to BBV152. In this case, vaccination was well-tolerated and there were no reported safety issues.[¹³]

A total of 25,800 subjects enrolled and randomized in a 1:1 ratio to receive the BBV152 vaccine and control. All participants were assessed for efficacy and safety endpoints and provided a Nasopharyngeal(NP) swab and blood sample before the first dose of IP. The NP swab and blood collected will be subject to RT-PCR and Anti-SARS-CoV-2 IgG antibodies. Participants who are found to be positive for either RT-PCR Or Anti-SARS-CoV-2 IgG antibodies will be excluded from the primary efficacy analysis. Figure 2 describes the clinical efficiency of COVAXIN. Phase III clinical trials demonstrating a short-term vaccination effectiveness of 81 percent for the COVID-19 entire virion inactivated vaccine candidate. A wide variety of candidate COVID-19 vaccines are being researched globally using different technologies and platforms in an effort to promptly and successfully combat the COVID-19 pandemic. These include vaccinations that are nucleic acid (DNA, RNA), protein subunit, nucleic acid (viral-vectored), live attenuated, and inactivated. Clinical trials have started for a few of these candidates. The National Institute of Virology (NIV) and the Indian Council of Medical Research (ICMR) collaborated on the development of COVAXINTM, an indigenous COVID-19 vaccine produced by Bharat Biotech (NIV). The BSL-3 (Biosafety Level 3) high containment facility at Bharat Biotech serves as the development and manufacturing site for this locally produced, inactivated vaccine. Drug Controller General of India (DCGI) granted approval for the vaccine's Phase I and Phase II human clinical trials as well as for an adaptive, seamless Phase I followed by a phase II randomised, double blind, multicenter study to assess the vaccine's safety, reactogenicity, tolerability, and immunogenicity (BBV152).

Figure 2: Clinical efficacy of COVAXIN

Clinical Trials

CDSCO granted restricted emergency approval to COVAXIN on January 3, 2021, based on Stage I/II immunogenicity tests as well as safety tests,[¹⁴] in the interest of the general public. Even though there was a lot of criticism and safety concerns, India initiated one of the biggest immunization campaigns for COVID-19 on January 16, 2021.[¹⁵] It is a 2-shot regimen that is delivered 4 weeks apart and is provided stable at 2°C–8°C in a ready-to-use, liquid formulation. A list of published COVAXIN clinical and preclinical research papers is included in Table 1. Preclinical findings in nonhuman primates and hamsters established the safety and protective effectiveness of the drug before it was tested in humans.

Table 1: COVAXIN clinical and preclinical investigations that have been published

Covishield

AstraZeneca and the University of Oxford co-created the COVISHIELD vaccine, which is called AZD1222, while the Serum Institute of India (SII) in Pune, Maharashtra, manufactures it. In human studies, the vaccination was shown to be safe, with no serious adverse effects observed at all. A significant T-cell and Ab response to the SARS-CoV-2 virus-causing COVID-19 has also been shown. It has shown a 62% effectiveness rate when two full dosages were administered to individuals in the studies. It was shown that the overall effectiveness of varied dose groups was 70%. As of the 3^rd week of January, AstraZeneca aimed to provide the UK with two million injections a week.[²¹]

Development and Efficacy

Pfizer BioNTech's mRNA COVID-19 vaccine gained reserve purpose permission on December 11^th, and Moderna received emergency use authorization (EUA) on December 18^th, while the UK MHRA authorized AstraZeneca's COVID-19 vaccine on December 30, 2020.[^22,23] Immunization efforts that began in December and started in January 2021 have even now revealed their efficacy in considerably lowering the number of fatalities, severe illnesses, and hospitalizations among those who got the vaccines.[²⁴] Four–five weeks after the 1^st shot of the AZD1222 (Astrazeneca) adenoviral vector vaccine and the BNT162b2 (Pfizer BioNTech) vaccine, a substantial reduction in hospitalizations due to COVID-19 has been identified.[²⁵] SARS-CoV2 vaccine, BNT162b2 (Pfizer BioNTech), has been found to generate T-cell and Ab retorts equivalent to those that are seen in people who are naturally infected.[²⁶] The immune response to BNT162b2 is inadequate after only 1 shot has been seen in certain patients, notably those with hematological malignancies, the SARS-CoV-2 virus, which makes them more susceptible to infection.[²⁷] There is a relationship between a British genetic mutation known as B.1.1.7 and an elevated risk of disease transmission and death.[²⁸] Both vaccines showed a little lower neutralizing action against B.1.1.7; they had no significant impact on vaccine effectiveness.[²⁹] Both vaccines' safety depends on whether or not adverse effects are discovered after the first or second dosage of the vaccination Figure 3.

Figure 3: Pfizer-BioNTech and Moderna vaccines' mechanisms of action diagram^[30]

Comparison Study

Two new COVID-19 vaccines, COVISHIELD from AstraZeneca and COVAXIN from Bharat Biotech, have been given the go light for an emergency launch in India. On Sunday, January 3, India's Drug Controller General of India (DGCI) gave the go-ahead. An important milestone has been reached in India's fight against the fatal spread of coronavirus, which has infected more than 10.3 million people in our nation alone. And with this emergency authorization, India seems to be on track to become the first country in South Asia to begin its mass vaccination campaign within the next few days. A variety of vaccinations and their characteristics are listed in Table 2.[³¹]

Table 2: A comparison study between different types of vaccines available

Sputnik V

The Gamaleya National Research Institute of Epidemiology and Microbiology (Russia) developed “Sputnik V” nCOVID-19 vaccine, which was previously used to treat Ebola and Mers. The effectiveness of Sputnik V in phase 3 testing was recorded as 91.6%. The Gamaleya Institute pronounced Sputnik V to be the most effective nCOVID-19 vaccine on April 21, only a few days after India approved it as the country's third nCOVID-19 vaccine. When it comes to protecting against nCOVID-19 infection, the “Russia's Ministry of Health said that the vaccine Sputnik V had an overall effectiveness of 97.6% in the globe[³²] and was 100% effective in avoiding severe cases.” “Sputnik V” nCOVID-19 vaccine preliminary conclusions had been available in The Lancet by Denis Logunov and colleagues.[³³] The results of the study demonstrated that the preventive effect was consistently larger in all participant age groups. For the expression of SARS-CoV-2 spike protein in Gam-COVID-Vac, Ad5 and Ad26 were used as vectors. To ensure that the population does not have any pre-existing adenovirus immunity, two distinct serotypes were administered 21 days apart. Gam-COVID-Vac is the only significant nCOVID-19 vaccine now in development that employs this strategy; others, With the Oxford–AstraZeneca vaccine, both doses are made from the same substance.[³⁴] Data from 1/2 of the studies, released in September 2020, showed that the immune system was working at a better degree of protection and led to a series of safe outcomes.[³⁵] Improper haste, corner-cutting, and lack of openness in data concerns have been blamed for the “Sputnik V” vaccination. This vaccine may be a viable approach for reducing nCOVID-19 infection since the data has been published and the scientific basis of vaccination has been explained. Like AstraZeneca's vaccine, it uses a viral vector as its delivery system (COVISHIELD in India). This nCOVID-19 vaccination, known as Sputnik V, is unique in that the two doses are not identical. A variety of “Sputnik V” derivatives, including normal liquids that can be stored at temperatures ranging from (2 to 8)°C, are currently being developed at the Gamaleya Institute. Adenovirus serotypes 26 and 5 are both used in the Gam-COVID-Vac vaccine, SARS-protein CoV-2's S-expressing gene has been added to this into the active compound of both vectors.[³⁶] There will be a compassionate use of this vaccination in Belarus and Argentina in December 2020.[³⁷] On January 21, 2021, Hungary became the first EU member to allow the emergency usage, as well as the UAE in the Gulf area. According to the Russian Direct Investment Fund, the Russian authorities agreed to register the “Sputnik V” in the European Union (EU) on January 19, 2021.[³⁸] EMA was urged by regional leaders in Germany on March 18, 2021, to expedite the approval of a Russian vaccine in order to avoid a severe shortage of effective vaccinations in the EU. As a result, German medical authorities have endorsed its use and described it as “brilliant” and “very safe.”[³⁹] Good immunogenicity data led to the April 12, 2021, compassionate acceptance in India of the “Sputnik V” vaccine for nCOVID-19.[⁴⁰]

Virafin

Medications, technologies, and therapies known as “compassionate” are now being tested in clinical trials for use in certain illness situations when there is no other therapy available.[⁴¹] An experimental medicine called “Virafin” has been put to compassionate use in the fight against the coronavirus pandemic that has just emerged. Due to the fast-upgrading of new nCOVID-19 cases in India in 2021, the DGCI on Friday, April 23, decided to allow the emergency use of Zydus Cadila's “Virafin” (Hepatitis C medicine made by Zydus Cadila) to treat adult patients with mild sign-symptoms.[⁴²] Zydus Cadila's “Virafin” has been authorized for EUA to treat mild cases of coronavirus in India.[⁴³] Phase iii drug trials are currently being conducted for this vaccine, and it has shown positive results for patients with nCOVID-19. There were several patients that received PegIFN-2b throughout the trials, and the results were negative after day 7 of therapy. SARS-CoV-2 protection provided by interferon-alpha has also just been reported in a prestigious publication. For those over 60 years old who cannot generate enough Interferon Alpha (INF-A), a lower level of INF-A may start to a better death threat for the patients in the study population with nCOVID-19. As a result of the Phase III study, a significant number of patients in the PegIFN-2b group showed a two-point statistically significant clinical improvement, and the need for oxygen supply and time to resolve signs and symptoms were knowingly lower in this group as compared to the those in the SOC group (5 days vs. 6 days). They found that the nCOVID-19 infection was effectively halted when this antibiotic was administered early on.[⁴⁴] Verafin was safe, effective, and tolerable at an early stage, and it had a significant therapeutic impact on moderately infected virus illness by reducing viral load and reducing oxygen supply.[⁴⁵] To control the nCOVID-19 disease more safely, a single dosage of “Virafin” administered through a subcutaneous regimen may be employed. During the drug's Phase-III clinical study, 91.15 percent of infected individuals with nCOVID-19 who were administered the bio-active recovered from the illness within 7 days of receiving the first dosage (claimed by Zydus Cadila). To treat nCOVID-19, a common medicine called 'Remdesivir' was employed. Favipiravir 200 mg (Glenmark Pharmaceuticals) is an antiviral medication that may be used to treat the virus. As a result, regarding the existing challenging environment, Zydus Cadila is optimistic that the recently announced “Virafin” would lessen the severity of the illness and, perhaps, cut fatality rates.[⁴⁶]

Common Adverse Effects of Taking Vaccines

Only until the safety of the COVID-19 vaccine has been established will it be made available. As with previous vaccinations, some people may have a minor fever, discomfort, or other adverse effects at the injection site. As one of the steps toward ensuring safe vaccination distribution to the people, states have been instructed to begin creating plans to cope with any COVID-19 vaccine-related adverse consequences. COVISHIELD^®: Tenderness at the injection site, arthralgia, headache, malaise, discomfort at the injection site, weariness, myalgia, chills, and pyrexia as well as nausea. There have been a few reports of demyelinating diseases after inoculation with this vaccine, but no causative association has been established. COVAXIN®: Discomfort at the injection site, tiredness, headache, sweating, fever, stomach pain, cough, body soreness, nausea and dizziness-giddiness, vomiting, tremors, colds, and swelling at the injection site are some of the minor symptoms of Adverse Events Following Immunization (AEFIs). There have been no additional major vaccine-related side effects documented. Paracetamol may be used to relieve mild side effects such as injection site discomfort, soreness, malaise, pyrexia, and other symptoms.[⁴⁷]

Evaluations of Clinical Growth

There is fresh information emerging as COVID-19 vaccine contenders go through drug testing, and this might assist in guiding future vaccine research efforts, including vaccine R and D strategy for upcoming epidemics. A goal product profile for COVID-19 vaccines has also been developed by the WHO, which gives recommendations for the design of clinical trials, execution, assessment, and follow-up [Table 3].

Table 3: Reported Phase III efficacy results for COVID-19 vaccine

Trial Design

Clinical COVID-19 outcomes in a placebo group must be accurately predicted in order to calculate a sufficient sample size for an effective clinical study. However, the rapidly fluctuating epidemiology of the COVID-19 pandemic makes it impossible to predict incidence rates, and the design of trials is further complicated by the influence of public health interventions such as social distancing and isolation on the virus's transmission.

Platforms and Goals for Technology

Traditional and cutting-edge technologies are used in the current COVID-19 vaccination pipeline [Figure 4]. Many vaccine platforms have shown encouraging T-cell and antibody responses, but it is too early to judge their effectiveness and potential. All 12 vaccine candidates under medical development use adjuvants. The COVID-19 vaccine pipeline now consists of a wide range of technological platforms, encompassing both conventional and cutting-edge methods [Figure 4]. Although impressive antibody and T cell responses have been reported for vaccinations based on several of the distinct platforms being used, it is still too early to judge their relative potential. Early results are already becoming available for the most advanced clinical candidates. Adjuvants are used by twelve vaccine candidates in the clinical stage. The spike (S) protein and its variations are the key antigens for the vast majority of vaccine candidates now undergoing clinical testing. Candidates that target N protein, attenuated vaccines, inactivated vaccines, and peptide vaccines are among those that are making progress. These candidates also target additional or multiple antigens. For a reliable sample size calculation in a typical clinical trial, a precise estimation of the background incidence rate of clinical COVID-19 end points in the placebo arm is necessary. Predicting incidence rates is difficult due to the COVID-19 pandemic's quickly shifting epidemiology, and the impact of public health measures to help prevent the virus' transmission, such as social isolation and quarantine, further complicates trial design.

Figure 4: COVID-19 vaccine candidates at various stages of research and based on different technological platforms.^[48] (a) Preclinical and exploratory pipeline. (b) The clinical pipeline. There are a variety of innovative techniques as well as more established ones, including the use of viral vectors such as DNA and RNA, recombinant proteins and peptide-based virus-like particles. Data collection and analysis are detailed in Supplementary Box 1

Status of Vaccine till Now

This vaccination has been administered to at least 58% of the world's population. 9.18 billion doses have been given worldwide, with an average of 31.9 million doses being provided daily. There are only 8.5% of families in low-salary nations who have accepted even a single shot of medication. The overall vaccination completion data are shown in Figure 5. This statistic was taken in January 2022, when the article was written. Vaccination continues globally beyond the deadline.[⁴⁹]

Figure 5: Ongoing vaccination update till Jan 2022

Vaccine Effectiveness

Vaccine effectiveness, as opposed to vaccine efficacy, refers to the decreased risk of illness or sickness among those who have been vaccinated. In March 2021, Public Health England published a study on the initial effects as well as efficacy of COVID-19 immunization with AZD1222 as well as BNT162b2 in England, estimating vaccine usefulness in contrast to mortality as well as hospitalization to be 81% and 80%, respectively.[⁵⁰] Between December 2020 and February 2021, a finding of the efficiency of AZD1222 or BNT162b2 compared to indications in 156,930 persons found that vaccination success was 70 percent in applicants aged 80 years or senior after the 1^st dosage, to a level of 89% 2^nd week after the 2^nd dosage.[⁵¹] The strategy utilized in the SIREN research[⁵²] may yield more trustworthy information on vaccine efficacy by considering vaccination coverage as a control. In the United Kingdom, on December 30, 2020, a decision was taken to postpone the second vaccination injection for 3 months following the 1^st, regardless of the vaccine used. For the sake of increasing the number of patients who could benefit from a first dose, this was a sensible approach. In the case of BNT162b2 and mRNA-1273, the 12-week period differed from the 3-week to 4-week intervals used in the efficacy trials.[⁵³] mRNA-1273 and BNT162b2 had lower antibody responses and vaccination effectiveness when administered in a single dose than when administered in two doses, which is not surprising.[⁵⁴] Approximately 12 weeks after getting a single BNT162b injection, antibody levels begin to fall. Just 91% (91%) of the time does BNT162b2 or AZD1222 give a significant degree of protection.[⁵⁵] People over 80 had higher antibody responses to BNT162b2, which is one advantage of delaying the second dosage by 3–12 weeks.[⁵⁶] Israel was one of the first nations to immunize a large percentage of its grown-up people. The national vaccination program began utilizing BNT162b2 on December 20, 2020. Priority was given to those with a high threat of difficulty, those who had COVID-19 before the vaccination campaign was swiftly extended to encompass everyone 16 and older in an effort to decrease the spread of SARS-CoV-2. Thirteen–twenty-four days after vaccination, preliminary findings suggested that a single dose of the vaccine was effective against new infections in 51% of patients.[⁵⁷] One dose of BNT162b2 was shown to be 46% effective in protecting against SARS-CoV-2, whereas a second dose given three weeks after the first dose was found to be 92% effective. As many as 1.2 million people were studied, and two doses of BNT162b2 decreased COVID-19 symptoms by 94%.[⁵⁸] BNT162b2 or mRNA-1273 vaccine injections in December 2020 and March 2021 protected 90% of health-care workers against infection.[⁵⁹] Among a large population of 49,220 US health-care workers, the BNT162b2 or mRNA-1273 vaccine had a 96% success rate, with a median age of 41 years.[⁶⁰] This includes [Figures 6, 7 and Table 3]. Vaccine efficacy (VE) may be affected by a variety of variables at both the individual and community levels, described in Figure 6.[⁶¹]

Figure 6: Vaccine efficacy is affected by a variety of factors

Figure 7: Efficacy of several COVID-19 vaccines

New Vaccines Still in Progress

International cooperation in the search for a safe and reliable vaccine is essential if the world is to benefit from a robust and efficient immunization program. In addition, a number of vaccinations are now being tested in Phase 2 or 3 studies. In the paragraph that follows, we will go through the basic concepts behind these vaccinations Table 4.

Table 4: List of new vaccines for the management of novel coronavirus

Cost Analysis of Vaccines

The COVID-19 vaccination is thought to be a key component in putting an end to the epidemic. Governments have to choose which vaccination to give to their populace. Analysis of cost-effectiveness in this decision-making process is seen to be useful. The cost-effectiveness analysis is used in this study to determine the extra cost per DALY avoided by vaccination versus no immunization for several COVID-19 vaccines. Even nations with access to the top COVID-19 vaccines are paying radically varying amounts for doses as the argument about vaccination equality in low-income countries continues. Throughout the outbreak, African countries have struggled to get enough vaccine supplies, and some are paying far more for doses than their rich counterparts. The most severely affected African nation, South Africa, is allegedly spending $5.25 per dosage of the AstraZeneca vaccine, compared to just $3.50 for European nations. The cost is significantly higher for Uganda, which allegedly pays $7 for each dosage of the two-shot vaccination from AstraZeneca. Moderna offered their vaccine to South Africa earlier this year for $30 to $42 per dosage, which was much more expensive than the $32 to $37 range paid by higher-income nations for the same vaccination. This summer, the government of Botswana also stated that the country is paying close to $29 per dose, a much higher price than those set for the US and EU. Colombia, a different nation particularly hard-hit by the virus, is paying $30 per dosage of the vaccine made by Moderna, which is double what the US has been asked to pay. The People's Vaccine Alliance conducted an analysis based on the anticipated manufacturing costs of Moderna and Pfizer's COVID-19 vaccines and discovered that Colombia may have overpaid by as much as $375 million for the combined vaccines produced by both firms. In contrast to the $3.50 paid by EU member states purchasing directly from the British vaccine manufacturer, Bangladesh, is apparently paying $4 for each dosage of AstraZeneca's vaccine produced by the SII. Although some of the costs agreed upon by governments and vaccine manufacturers are made public, there is often a lack of openness in vaccine supply agreements, making it difficult to examine and comprehend the differences in costs incurred by affluent and less fortunate countries.[⁷³] Everyone 6 months of age and older can receive a COVID-19 immunization at no cost. No of their immigration status or health insurance coverage, everyone residing in the United States will receive free vaccinations that were purchased with tax cash. A single COVID-19 vaccine's cost is expected to vary widely depending on a number of variables including time, location, and current contracts. Some of the agreements made with governments or other funding organizations, like the Coalition for Epidemic Preparedness Innovations, may have had some pricing constraints (CEPI). This may also depend on whether the pandemic is still active or not, with businesses hiking at-cost pricing to increase profits after the majority of outbreaks are contained. Furthermore, where the vaccine is being bought will also determine the price, with lower and middle income countries likely paying much less than developed countries.[⁷⁴] With the US Department of Health and Human Services and the Department of Defense, Pfizer (US) and partner BioNTech (Germany) have announced an advance purchase agreement to supply 100 million doses of their COVID-19 vaccine candidate, BNT162, for USD1.95 billion. MUMBI, 9 April (Reuters) Given that all adults would be given booster doses of the COVID-19 vaccine, SII and Bharat Biotech have reduced the cost of their respective vaccinations. For private hospitals, the price of SII's COVISHIELD will decrease to 225 rupees ($2.96) each dosage from 600 rupees. With 1,150 new cases reported in the last 24 h and 83 fatalities, infections in India have reached their lowest point in over 2 years. 521,656 people have died nationwide since the outbreak began. The COVID-19 vaccine made by SII, the largest vaccine manufacturer in the world, is sold under the trade name COVISHIELD by AstraZeneca (AZN. L). India has administered 1.85 billion vaccine doses to its 1.35 billion inhabitants, with COVISHIELD accounting for 82% of those. The government has set a limit of Rs. 150 for the service fee that commercial COVID vaccination clinics may charge to provide the preventive dosage. This is in addition to the price of the vaccination. SII and Bharat Biotech, the main two producers of the COVID-19 vaccine in the nation, have reduced the cost of COVISHIELD and COVAXIN for private hospitals to Rs. 225 per dose, respectively. Previously, COVISHIELD was priced at Rs. 780 every treatment, while COVAXIN cost Rs. 1,200 per dose at private facilities, plus a Rs. 150 service fee.[⁷⁵]

Adverse Event Following Immunization Monitoring Process

People are becoming more worried about the hazards connected with vaccinations as the number of infectious illnesses that may be prevented by vaccination continues to drop. In addition, as knowledge about vaccinations has grown and technology has advanced, studies on the safety of current vaccines have been conducted, which occasionally has raised concerns. Any unfavorable medical occurrence that occurs after immunization but does not necessarily have a causal connection to the use of the vaccine is referred to as an adverse event post immunization. Uncertainty about a vaccine, if not quickly and adequately addressed, can have negative effects on vaccination coverage and disease incidence. If, on the other hand, healthy people have vaccine-related adverse effects, they should be quickly reported so that further investigation and necessary action may be taken. WHO has formed a Global Advisory Committee on Vaccine Safety to respond swiftly, effectively, and scientifically to vaccine safety concerns. It is any undesirable medical event that develops after vaccination and is not always directly related to the use of the vaccine. AEFI Reporting Categories.[⁷⁶]

• Minor AEFI: These are modest, common, self-limiting effects, such as discomfort and swelling at the injection site, fever, agitation, and malaise
• Severe AEFI: These are more severe nonhospitalized instances that do not persist over time but may be incapacitating. Examples include recovered nonhospitalized allergy patients, high fever (>102°F), hypotonic hyporesponsive episodes, and sepsis
• Serious AEFI: entail after-vaccination occurrences such hospitalizations, clusters, impairments, media attention, and public angst. Any mild, severe, or serious AEFIs must be reported using the Co-WIN app by the vacciner or the CVC management. Significant and severe AEFIs must also be reported in writing and by phone to the district immunization officer very once
• At work place CVC: Team Lead (medical officer) will ensure management of anaphylaxis/AEFIs as Work Place CVCs and referral to AEFI center (if needed).
• A basic life support (BLS) ambulance: must mandatorily be deployed at the WorkPlace CVC and should be utilized for shifting beneficiaries to the linked AEFI management center if required
• Anaphylaxis kit: The team leader or supervisor (a medical professional) shall see to it that an anaphylaxis kit is available at the vaccination center and that all of its components are up to date on their expiration dates.
• AEFI management:
1. All Work place CVC will have a medical officer as supervisor/team leader
2. All workplace CVC will be equipped with an anaphylaxis kit for handling any adverse events, and they will be connected to the closest health-care facility (the AEFI Management Center) in case a referral for possible postvaccination medical management is necessary. Less than an hour should be needed to go from WorkPlace CVC to the AEFIs management facility
3. At the WorkPlace CVC, a BLS ambulance must be deployed by law. If necessary, it should be used to transport beneficiaries to the associated AEFI management center.

Adverse Events Following Immunization Detection -to Strengthen Vaccine Safety Monitoring in All Countries

The first step in ensuring that vaccines are safe and are delivered safely is effective spontaneous reporting of adverse events following vaccination (AEFI). Yet approximately half of the world's population resides in nations with ineffective vaccination safety monitoring systems. Since severe responses after vaccination are so uncommon, numerous nations have teamed together to combine their AEFI data in a single worldwide database. The WHO Programme for International Drug Monitoring is in charge of maintaining the database. The majority of severe AEFI are not actually vaccine responses, according to experience; rather, they are unrelated health issues or vaccination-related concerns. The objective is for all nations to at the very least have a framework in place for examining significant AEFI that are reported on their own. Vaccine pharmacovigilance should be strengthened in nations that produce vaccinations and those that introduce newly available vaccines.[⁷⁷] Figure 8 describes the AEFI monitoring steps in details.

Figure 8: AEFI monitoring process. AEFI: Adverse event following immunization

Pre vs. Post-marketing of COVID-19 Vaccine Safety

In order to gather as much information as possible and increase the likelihood of identifying truly suspicious events whose nature is important to understand or which have never been observed before, it is important to investigate every event that occurs after a vaccination. This will help determine whether there is a causal relationship between the vaccination and the observed event. By validating what was shown in trials before authorization and perhaps discovering new possible adverse events, especially if they are rare (1 in 10,000) and very infrequent, regulatory bodies like AIFA can validate the safety of vaccinations in the real world (less than 1 in 10,000). Therefore, a larger number of reports does not always mean that the vaccination is more risky; rather, it shows how well the pharmacovigilance system is able to monitor safety. Out of a total of 1,564,090 doses delivered for both vaccinations as of January 26, 2021, a total of 7,337 reports have been recorded in the RNF, representing a reporting rate of 469 per 100,000 doses1. The majority of reports concern Comirnaty, the most often used vaccination (7,294 out of 1,550,019 doses delivered), with a cumulative reporting rate of around 471 reports per 100,000 doses administered (i.e., not discriminating between first and second dosage). The lower number of reports entered for the Moderna vaccine (39 out of a total of 14,071 doses administered, with a reporting rate of approximately 277 per 100,000 doses) is due to its recent introduction on the market and the consequent lower use. These preliminary values will have to be re-evaluated over time and do not allow to compare the safety profile of the two vaccines. In fact, it's critical to keep in mind that a high reporting rate is a sign of high reporting sensitivity and underscores the significance of this act for the investigation of medication safety. Regardless of the dosage and vaccination given, the reporting rate is 561/100,000 doses delivered to females and 293/100,000 doses supplied to males. The enhanced sensitivity to reporting by vaccinated women, a feature also observed in the spontaneous pharmacovigilance of various vaccines and medications, may have an impact on these values. Approximately 85% of the time, the response happened the day of or the day following the immunisation. Rarely did the incident continue into the next 48 hours. To properly identify the temporal link between vaccination and the occurrence of the reported incident, more evidence is required in less than 5% of instances. The majority of the reports from the first month of the immunisation programme (92.4%) were unimportant incidents, with a reporting rate of 434/100,000 doses given. Since 99% of the reports and doses administered can be attributed to the Comirnaty vaccine (the reporting rate of non-serious events for the Moderna vaccine is 270/100,000 doses administered, extrapolated on the basis of only 14,000 doses actually administered), the rate for the Comirnaty vaccine is comparable to the cumulative figure in this instance as well. Regardless of the vaccine type, provided dose (I or II dose), or potential causative involvement of the immunisation, serious reports make up 7.3% of the total and occur at a rate of 34 serious events per 100,000 doses delivered. The interval between the delivery of the vaccine and the beginning of major adverse events exhibits a pattern that is consistent across all reports. A vaccine and a temporally associated event may be linked by a causal relationship based on the evidence that is currently available, but this evaluation of the causal role of vaccines in such reports requires specific investigation for each individual case and may involve asking the reporter for additional information. The majority of Moderna vaccine-related adverse events which are mostly fever, asthenia/fatigue, and injection site pain—relate to the system organ class of general disorders and administration site conditions and are rated as non-serious in 97% of cases. The events that are classified as musculoskeletal system and connective tissue disorders occur in the following order of frequency, with widespread joint and muscle pain being classified as non-serious in 94% of cases while nausea and abdominal pain are classified as non-serious in 90% of cases for gastrointestinal disorders. 14 reports of anaphylaxis/anaphylactic shock due to the Comirnaty vaccination were made during the time period under consideration, with 1 duplicate case being reported by both the vaccine provider and the firm. With an average age of roughly 45 years, there are 12 instances involving female individuals and 1 case involving a male subject. Every report describes what happened right away following the first injection of the vaccination. In 85% of instances at the time of reporting, the result was complete recovery or improvement.[⁷⁸]

Types of Safety Surveillance Systems for Vaccines

Continual vaccination safety monitoring is a difficult procedure. Safety testing for vaccines must be proactive, rapid, rigorous, and impartial. Adverse events following immunisation (AEFI) are defined by the World Health Organization (WHO) as any unfavourable medical occurrence that occurs after immunisation but does not necessarily have a direct connection to the use of the vaccine. Any undesirable or unanticipated sign, aberrant test finding, symptom, or illness may qualify as an adverse event. To arrive at a sound conclusion, case definitions must be created and a sequence of organised procedures must be followed.[⁷⁹] The four primary surveillance techniques are passive (automatic), active, cohort event monitoring (CEM), and sentinel. For AEFI, it is essential to upgrade the global vaccination safety surveillance mechanisms already in place. Even though adverse events of special interest (AEFIs) are mostly collected through passive systems, nations with more advanced systems should take into account active surveillance. All interested parties should be involved in improving vaccination safety monitoring. After notice, inquiry, analysis, causation determination, and communication, the system should incorporate capabilities for data gathering and reporting. In active surveillance, the authorised staff members visit healthcare institutions, interact with healthcare professionals, check patient records, look for potential AESI cases, and collect and evaluate data in accordance with a predetermined procedure. The benefits of this system include better sensitivity and the ability to be utilised for signal detection, calculating the frequency of an event within a certain population, and calculating the relative risk of the occurrence. Without using blinded observers, it is time- and resource-consuming, has inferior coverage, and is subject to bias. The uncommon thrombosis with thrombocytopenia syndrome (TTS), which results in atypical blood clots linked to low platelet counts, was also related to VigiBase®. But the exact process behind its occurrence is still not known. Age and gender of females were noted as identified risk factors for TTS. Reviewing the current information points to a causal connection between TTS and adenoviral vector vaccinations (such as those made by AstraZeneca and J&J), but not with the mRNA COVID-19 vaccines.[^80,81] The risk of TTS with the AZ vaccination was estimated to be 1 case per 250 000 in the UK and 1 case per 100 000 in the European Union (EU).

COVID-19 Vaccine Boosters

Booster doses of the COVID-19 vaccine can further improve or restore immunity that may have waned over time following your first series immunisation. When people receive their COVID-19 immunizations as advised, including all necessary boosters when appropriate, they are most protected against serious COVID-19 disease. For those who are either mildly or severely immunocompromised, distinct COVID-19 vaccination recommendations exist[⁸²] [Table 5].

Table 5: Booster dose vaccine different ages

Precaution Dose or Third Dose

To strengthen protection against COVID-19 infection, the third dosage of the COVID-19 vaccine is administered six months following the second dose. After the initial vaccination of the first two doses, an ICMR research found that antibody levels start to decline after around six months. The immune response is further boosted and the antibody count is raised with the third dosage, which enhances defence against a severe COVID-19 infection. Frequent adverse effects of a precautionary dosage of COVID-19 include fever, headaches, bodily discomfort, etc. Although there have been cases of thrombosis recorded in the past, scientists believe that the vaccine's advantages exceed its drawbacks.[⁸³]

Precaution Dose Taken in India

Despite government efforts to expand vaccination coverage in India, fewer than 1% of the 77.1 crore-strong target population in the 18- to 59-year-old age range has received the recommended dosage. Nevertheless, 25.84% of the 16.8 crore eligible people in the 60+ age group as well as frontline healthcare staff have got the precautionary dosage. On January 10, 2022, the prophylactic dosage was introduced for the first time in India due to an upsurge in illnesses. Frontline employees and seniors over 60 years old who have comorbidities were the first to experience it. The precaution dose is now available to all residents over the age of 18.

Conclusion

The wide range of vaccinations on the market might make it difficult to make an informed decision because of the unique features of both vaccines and patients. In many nations, there are still many unanswered issues about the absence of adequate dosages and other criteria for prioritizing research. Series A vaccinations are more effective but also more costly than series B vaccinations, for example, due to the effectiveness of vaccines. Another issue is the time it takes for primary care physicians and pharmacists to become involved in the vaccination distribution process. Even if a vaccination campaign is successful, it should be thoroughly reviewed by looking at the doses of vaccination, vaccine administration methods, vaccine alternatives, and the issue of viral changes that might lead to vaccine failures in the future. Keeping track of all of these elements is critical to the overall effectiveness of an action plan. COVAXIN's safety and efficacy have been shown in several studies. A similar level of efficacy against mutant SARS-CoV-2 strains has been established with COVAXIN. COVAXIN has been shown to be safe and immunogenic in adults, adolescents, and the elderly. The first efficacy of COVID-19 vaccines well exceeds the minimal acceptable requirement for approval stated by the WHO and FDA. Publication and peer evaluation of the results of the COVAXIN Phase-III clinical study are, nevertheless, requirements in order to improve transparency and promote trust in indigenously generated vaccines, and to dispel COVAXIN hesitation among the general population. Vaccines against new coronavirus have been approved for compassionate use by a number of governments.

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Acknowledgment

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