COVID-19 infection is caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) [1]. The impact of COVID-19 was far- reaching worldwide, including more than150 countries. Thus, the WHO declared this disease a global pandemic [2].Vaccination is a simple, safe, and effective way of preventing harmful diseases. The vaccine administration uses the body's natural defense system to build resistance tothe specific infection and strengthens the immune system [3].COVID vaccination is now offering a way to transit out of this phase of the pandemic. Two vaccines have been granted by the Central Drugs Standard Control Organization (CDSCO) in India: Covishield and Covaxin. India's Bharat Biotech develops Covaxin, the Indian Council of Medical Research (ICMR), and the National Institute of Virology (NIV). Itis an inactivated vaccine. The Generic name of Covaxin is BBV152 [4]. It is given as an intramuscular injection into the deltoid muscle of the upper arm in two doses with an interval of 4–6 weeks. The common ADRs observed are injection site pain/swelling/redness/itching, fever, headache, body pains/Malaise, nausea, vomiting, and rashes [5]. A Survey conductedby Swayam Pragyan Parida et al. has shown that pain at the injection site followed by fever and Myalgia were the most common ADRs of Covaxin[6].

Covishield is a recombinant replication-deficient chimpanzee adenovirus vector encoding the SARS CoV 2 spike glycoprotein. It is a viral vector vaccine. It is developed by the serum institute of India on the same patenttechnology as AstraZeneca. The Generic name of Covishield is ChAdOx1to-19 (Serum Institute of India), AZD1222 (AstraZeneca) [7]. It is administered intramuscularly into the deltoid muscle in two doses at a volume of 0.5 ml each with a time interval of 12–16 weeks. The ADRs observed are injection site tenderness, warmth, pain, redness, itching, swelling or bruising, being unwell, tired (fatigue), fever with or without chills, headache, feeling sick, nausea, joint pains, or muscle ache [8]. A survey conducted by Maria Jose et al. at a tertiary care hospital in Kerala has resulted in ADRs such as fever, tiredness, pain at the injection site, chills, Myalgia, and headache [9]. According to WHO, Adverse Drug Reaction is “Any response to a drug which is noxious and unintended which occurs at normal doses used in man for prophylaxis, diagnosis or therapy of disease or the modification ofthe physiological function”. This definition excludes overdose that may beaccidental or intentional, treatment failure drug abuse. An adverse event is “any unwanted medical occurrence during drug administration”. When an ADR is suspected, the assessment should include the collection of data, including demographics of the subject experiencing ADR, a list of all medications used at the time of ADR occurrence, and details of ADRs liketime of onset, its duration, severity, treatment and outcome of the treatment. This data must be used to assess the relationship between the drug and suspected ADR. This assessment can be done by one or more standard ADR scales like the WHO and Naranjo's assessments [10].

2.1 About Covid-19 virus (Corona virus) :

COVID-19, also called coronavirus disease 2019, is a sickness caused by a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2).Coronavirus is a family of viruses that can cause illnesses such as the common cold, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).Many people with COVID-19 have mild to moderate symptoms and can recover on their own. But COVID-19 can serious illness and lead to death in some people. People at higher risk include older adults, and the risk increases with age. Also at higher risk for serious illness are people with existing medical conditions. Getting a COVID-19 vaccine helps prevent serious illness, the need for hospital care due to COVID-19 and deathfrom COVID-19.[11]

2.2 Vaccines:

Vaccines by definition are biological agents that elicit an immune response to aspecific antigen derived from an infectious disease-causing pathogen. Edward Jenner developed the first vaccine in 1796 using cowpox to inoculate against smallpox.[12]

         
           
       
Fig.1- Vaccines Included in this Review

1. Covishield :

Serum Institute Of India In Lines With The Oxford-Astrazeneca, Chadox1(Covishield) Developed At Oxford. This Is The First Multi-Centric Studyto Assess The Safety Of The Indigenously Prepared Covishield Vaccine In India

2. Covaxin :

Covaxin Is An India's Indigenous Covid-19 Vaccine By Bharat Biotech Is Developed In Collaboration With The Indian Council Of Medicalresearch (Icmr) - National Institute Of Virology (Niv). The Vaccine Received Dcgi Approval (Drug Controller General Of India) For Phase I & Ii Human Clinical Trials In July, 2020. Covaxin® Demonstrated 81% Interim Efficacy In Preventing Covid-19 In Those Without Prior Infection After The Second Dose.

3. Sputnik-V :

Sputnik V Is The World's First Registered Vaccine Based On A Well-Studied Human Adenovirus Vector Platform. It Has Been Approved For Use In 71 Countries With A Total Population Of 4 Billion People. The Vaccine Is Named After The First Soviet Space Satellite.

4. Moderna Spikevax :

Spikevax Is A Vaccine For Preventing Corona Virus Disease 2019 (Covid-19) In Peoplefrom The Age Of 6 Months. The Originally Authorised Spikevax Contains Elasomeran, A Molecule Called Messenger Rna (Mrna) With Instructions For Producing A Protein From The Original Strain Of Sars-Cov-2, The Virus That Causes Covid-19.

5. Novavax :

Novavax Is Produced By The Serum Institute Of India Under Licence From Novavax And Is Part Of The Covax Facility Portfolio, Giving A Much- Needed Boost To Ongoing Efforts To Vaccinate More People In Lower- Income Countries.

6. Gemcovac-19 :

It Is An Indigenously Developed Mrna Vaccine In India Developed Primarily By Genova Biopharmaceutical Limited Which Is Part Of Emcurebiopharmaceutical 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.

7) Vaxzevria :

Vaxzevria Is A Vaccine For Preventing Coronavirus Disease 2019 (Covid-19) In People Aged 18 Years And Older. Vaxzevria Is Made Up Of Another Virus (Of The Adenovirus Family) That Has Been Modified To Contain The Gene For Making A Protein From Sars-Cov-2, The Virus That Causes Covid-19. Vaxzevria Does Not Contains The Virus Itself And Cannot Cause The Covid 19 Infection To The Particular Contacted Persons

4. Details On Adrs And Stability Of Covid-19 Vaccines :

4.1 Covishield :

 It Was Developed In The United Kingdom By Oxford University And British Swedish Company Astrazeneca, Using As A Vector The Modified Chimpanzee Adenovirus Chadox1.[13]

1. Contents:

Chadox1 Ncov-19corona Virus Vaccine (Recombinant) Contains Anon- Replicating Virus ( A Weakened Chimpanzee Adenovirus That Causes Common Cold) Ie. Genetically Engineered To Produce Coronavirus Proteins In The Body.[14]

2. Adverse Drug Action :

The Adverse Drug Reaction Of Covishield Vaccine Include Reactions The Site Of Injection(Such As Pain, Swelling, And Redness), Headache, Nausea, Vomiting, Muscle Pain, Joint Pain, Fatigue, Malaise (General Discomfort), Fever, Chills, And Flu-Like Symptoms. Most Of These Side Effects Are Mild And Temporary (Subside Within 2-3 Days) That Subside On Their Own.If Required, You May Take Paracetamol To Provide Symptomatic Relief. However, If These Persist (Symptoms Continue Beyond 2-3 Days) Or Get Worse, The Doctor Know. [14][15]

3. Stability:

Covishield Can Be Stored A 2-8 Centigrade, Which Is A Household Refrigerator Temperature. This Makes The Vaccines Most Suited Conditions As Most Of The Vaccines Here Are Kept At The Same Temperature Range.[16]

4. Contraindications :

As With Other Intramuscular Injections, Covishieldtm Should Be Given With Caution To Individuals With Thrombocytopenia, Any Coagulation Disorder Or To Persons On

Pregnancy :

There is a limited experience with the use of ChAdOx1 nCoV-19 CoronaVirus Vaccine (Recombinant) in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or post-natal development; Administration of COVISHIELD™ in pregnancy should only be considered when the potential benefits outweigh any potential risks forthe mother and fetus.[19][20]

Breastfeeding Anticoagulation Therapy, Because Bleeding Or Bruising May Occur Following An Intramuscular Administration In These Individuals.[17] Fertility, Pregnancy And Lactation Fertility Animal Studies Do Not Indicate Direct Or Indirect Harmful Effects With Respect To Fertility.[18]

It is unknown whether COVISHIELD™ is excreted in human milk.[21]

The expiry date of vaccine is indicated on the label and packaging. Once opened, multi-dose vials should be used as soon as practically possible and within 6 hours when kept between +2°C and +25°C. All opened multidose vials of COVISHIELD™ should be discarded at theend of immunization session or within six hours whichever comes first.[18]

6. Special precautions for storage :

Store in a refrigerator (+2°C to +8°C). Do not freeze. Keep vials in outercarton to protect from light. Discard if vaccine has been frozen. Opened multidose vial (After first use)For storage conditions after first opening of the medicinal product, seesection 6.3.[20]

7. Nature and contents of container :

COVISHIELD™ is supplied as ready to use liquid in rubber-stopperedmultidose vial and single dose vial as1dose-0.5 ml per vial, 2dose-1.0 ml per vial,5 dose 2.5 ml per vial,10 dose 5.0 ml per vial,20 dose-10 ml per vial [22] After first opening, multi-dose vials should be used as soon as practicallypossible and with hours when kept between +2°C and +25°C. Discardany unused vaccine.[23]

4.2 Covaxin :

Country: COVAXIN, which is an indigenous COVID-19 vaccine to fightagainst corona virus, has been developed by Bharat Biotech in collaboration with Indian CouncilMedicalResearch (ICMR) and [24]

1. Content :

COVAXIN® includes the following ingredients: COVAXIN® contains 6µg of whole-virion inactivated SARS CoV-2 antigen (Strain: NIV-2020-770), and the other inactive ingredients such as aluminium hydroxide gel (250 µg), TLR 7 /8 agonist (imidazoquinolinone) 15 µg, 2-phenoxyethanol 2.5 mg, andphosphate buffer saline up to 0.5 ml. The vaccine (COVAXIN® ) thus has been developed by using inactivated/ killed virus along with the above mentioned chemicals.[25]

2. MOA :

vaccines confer passive immunity against SARS-CoV-2 by raising antibodies against the Spike(S) protein. Both vaccines delivermRNA encoding the entire S protein with 2 equal proline substitutions for stability. An equal amino acid substitution is one thatexchanges one amino acid for another biochemically similar one[26][27]

3. Adverse Drug Reactions :

Bharat Biotech also listed the risks/sideeffects of Covaxin. These include: "Injection site pain, sites welling,site redness, site itching, stiffness in the upper arm, weakness in injection arm, body ache, headache, fever, malaise, weakness, rashes, nausea, vomiting"[24] One of the study aimed to assess the adverse events following COVID?19 vaccine (Covaxin) immunization at a tertiary care institution and also assess the predictors of the adverse events following immunization (AEFI). The prospective observational study was conducted in a tertiary care institute among the Covaxin beneficiaries between June 28 and September 6, 2021. A total of 1826 participants were assessed for any local or systemic adverse events after seven days of vaccination. A telephonic interview was conducted, and the beneficiaries were assessed according to the adverse event grading. A total of 1826 participants were assessed for AEFI, and 544(29.8%) reported at least one of the AEFI. No severe adverse events were reported, and about 1.6% had moderate AEFI. Pain at the injection site (14.6%), fever (9.7%), and myalgia (5.9%) were the common adverse events reported by the participants. AEFI incidence was higher in the first dose (38.1%) when compared to the second dose (26.4%), and this finding was significant witha p < 0>

4. Stability :

COVAXIN® is presented in USP type 1-glass vials. Single dosevial - 0.5mL Multi dose vial - 2.5mL (5 dose) Multi dose vial - 5.0mL (10 dose) Multi dose vial - 10.0mL (20 dose) Opened vials may be used in subsequent immunization session for up to a maximum of 28 days provided that all of the following conditions are met (as described in the WHO policy statement: Multi-dose vial Policy (MDVP) Revision 2014 WHO/IVB/14.07). [31][32] The expiry date of the vaccine has not passed .The vaccine is approved for use for up to 28 days afteropening the vial as determined by WHO. The vaccine vial has been, and will continue to be, storedat+2°C to +8°C

4.3 Sputnik-V :

1. Country :

Country Developed by Russia's Gamaleya National Centre ofEpidemiology

2. Content :

Components 1^st dose each dose of 0.5ml contains stereo type 26 (recombinant) Adenovirus particles containing SARS-COV-2 Protein 5 gene (1.0+=0.5) x 1011 component 2 – 2^nd dose – each dose of 0.5ml contains stereo type 5(recombinant) Adenovirus particles SARS-COV-8 protein(1.0+=0.5) x 1011 [35]

3. Adverse drug reaction :

flu like syndrome can be observe and the patient may suffer from headache, fatigueand injection site reaction also observed [36]

4. Stability/Storage :

Frozen preparation : &store frozen (-18°c) for Vaccine administration once product removed from freezer (- 18°c) it ib kept at room temps until completely thawed and to be used within 2 hours Once thawed gently shake well vial Solid lyophilized powder for don't shake Sharply Vaccine can kept at 2-8°C, Refreezing is not allowed.[37]

5. Shelf life :

Frozen preparation - approved shelf life life for both Component (1&2)  is6months kept at 18°c (in dark place) .Liquid preparation - This prep is (under research prep – The lyophilized powder form of Vaccine can be kept at 2-8°c.The Expiry date of Vaccine in indicated[38]

Who should NOT receive Sputnik Vaccine?

Individuals having fever at the time of coming for vaccination (Can berescheduled after the illness is settled) Patients with active COVID-19Those with mild COVID-19 can receive the vaccine once the isolation period complete. Those with severe COVID-19 can receive the vaccine once they become stable Individuals who had severe post vaccination complication with component Ishould not receive component II [40]

6. Vaccine Administration :

Route of Administration: Intra-muscular Site of Administration: Deltoid Muscle(Upper Arm), Non dominant sideDose: 2 doses (21 days apart) Presentation: 0.5ml Single dose ampoule/ 05dose vial (3ml) [41][42]

7. Special Warnings and Special Precautions:

Vaccine should be taken after consultation with your physician to weigh possible benefits over risks.

8. Hypersensitivity :

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of anaphylactic event following the administration of the vaccine.

9. Concurrent Illness :

As with other vaccines, administration of Sputnik V should be postponed in individuals suffering from an acute severe febrile illness. However, the presence of a minor infection, such as cold, and/or low-grade fever should not delay vaccination Thrombocytopenia and Coagulation Disorders Sputnik V should be given with caution to individuals with thrombocytopenia, any coagulation disorder or to persons on anticoagulation therapy, because bleeding or bruising may occur following an intramuscular administration in these individuals.[43]

Immuno-compromised Individuals It is not known whether individuals with impaired immune responsiveness, including individuals receiving immunosuppressant therapy, will elicit the same response as immune- competent individuals to the vaccine regimen. Immuno- compromised individuals may have relatively weaker immune response to the vaccine regimen. Individuals on short-term immune-suppressive medication should wait for 28day after the medication ends. Those chronically immune-suppressed may receive the vaccine, though efficacymay be uncertain (Ref: leaflet insert) Those post-transplantation may receive the vaccine 3 months after transplantation Those post chemotherapies may receive the vaccine 28 daysafter chemotherapy[44]

10. Duration and Level of Protection :

The duration of protection hasnotyetbeenestablished. Aswithanyvaccine, Sputnik Vmaynotprotectall vaccine recipient [45]

4.4 Moderna Spikevax :

1.Country ;

It is developed by a Famous American Company MODERNA. Moderna is a Biotechnology company that focus on the development of messenger RNA (mRNA) therapeutics and vaccines. The company develops and discovers drugs that produce proteins or antibodies in patients cell.[46]

2.Contents :

The Moderna Spikevax is a mRNA vaccine which composed of Nucleoside modified mRNA Encoding. It is a spike protein of sever acute respiratory syndrome of coronavirus (SARS-CoV 2)[47].

3.Adverse Drug Reactions :

It is further classified according to its occurance-

Commonly Seen- Redness Soreness and Swelling at the site of injection is seen in some patients after the administration of the vaccine within the time period of 24hrs.ChillsFatigue, Joint pain, headache, mild fever, muscle aches, enlarged lymph nodes are also commonly seen is patients.[48]

Rarely Seen - Myocarditis It is a condition in which Inflammation to Heart Muscles Occurs. Pericarditis-It is a condition in which Inflammation to Outer Lining of Heart Occurs. These 2 conditions are rarely occurs in some patients.[48]

4.Stability :

Spikevax is a Suspension type dosage form administered Intramuscularly. It should be stored at 2-8 degree Celsius. If the vaccine gets favorable conditions then it can stored for upto 30 days It should be protected from light. And we should not shake the vial.[49].

5.Researches :

Brown University researchers conducted the largest head-to-head comparison study of the two mRNA vaccines approved by the U.S. Food and Drug Administration — the Moderna and Pfizer-BioNTech vaccines. The result, published in JAMA Network Open, showed that for older adults, the Moderna vaccine was associated with a slightly lower risk of adverse events than the Pfizer-BioNTech vaccine. The results of this study can help public health experts weigh which mRNA vaccine might be preferred for older adults and older subgroups, such as those with increased frailty,” said lead study author Daniel Harris, an epidemiologist and research scientist in the Center for Gerontology and Healthcare Research at the Brown University School of Public Health .The study looked at more than six million older adults, with the average age of 76years, who were vaccinated against COVID-19 using one of the two mRNA vaccines, Moderna and Pfizer- BioNTech. The vaccines have subtle differences in manufacturing, administration and immune response .The study confirmed that for older adults in both vaccine groups, the risk of serious adverse events was very low. The researchers also observed that for these older adults, the Moderna vaccine was associated with a 4% lower risk of pulmonary embolism, which is a sudden blockage in blood vessels of the lungs, and a 2% lower risk of thromboembolic events, defined as several conditions related to blood clotting.[50]

4.5 Novavax :

1. Country :

It is developed by The Serum Institute of India which is famous for its vaccines like Covishield.[51]

2. Contents :

NOVAVAX is a Recombinant Spike Protein vaccine which is in the formof NANOPARTICLES and at the time of administration it is further converted into Suspension for injection. A single dose contains about 0.5 ml.[52]

3. Adverse Drug Reactions :

Nausea and Vomiting are observed after some time of administration Headache are common in some young volunteers but Dizziness are rarely seen in some peoples. Itching is rarely seen in some peoples but Tenderness, Swelling and Erythema at the site of administration are common.[53]

4. Stability :

Novavax is a Suspension type of formulation which is made with mixing the nanoparticles with the water for injection. Store the prepared vaccine under the temperature ranging from 2-8 degree Celsius Do not shake the vials After opening the vials used it within 6 hours practically.[54]

5. Researches :

Clinical trials have demonstrated the efficacy of NOVAVAX[55], but the adaptive immune responses to the vaccine have not been characterized in detail. Six rhesus macaques were immunized with NOVAVAX at weeks 0 and 4. The animals were boosted with NOVAVAX, a variant COVID-19 vaccine based on the P.1 (Gamma) S seven months after dose 2, at week 35.Blood, bone marrow and bronchoalveolar lavage (BAL) were frequently sampled during the study period. Two weeks after the first immunization, all animals developed detectable S-binding IgG and neutralizing antibodies in the serum . The second immunization significantly amplified the response, with neutralizing titers exceeding WHO international standard by ~10- fold. The third immunization with variant S antigen boosted the systemic antibody responses above the levels measured after the second dose. S- specific bone marrow resident plasma cells were detected in all animals both at weeks 39 and 55 , suggesting that a durable plasma cell pool was established after three immunizations. The mucosal antibodies in the lungs, quantified as S-binding IgG antibody titers in the BAL fluid, were detectable after two immunizations (week 6) and further boosted by the thirddose (week 37), resembling the kinetics of serum antibodies.[55][56]

4.6 Gemcovac-19 :

1. Country :

Gemcovac-19, the first mRNA Covid-19 vaccine developed in India.with funding support from Department of Biotechnology (DBT)and Biotechnology Industry Research Assistance Council (BIRAC). Afew days ago this vaccine got the nod from the office of the Drug Control General of India (DCGI) for Emergency Use Authorization (EUA).GEMCOVAC-19 is the very first mRNA vaccine developed inIndia and only third mRNA[57]

2. Adverse Reactions :

3. Stability :

GEMCOVAC®-19 is stable at 2–8 °C and can be considered superior in termsof deployability in India and other developing nations (especially LMICs) compared to other approved mRNA vaccines. In GEMCOVAC®-19, the mRNA is adsorbed on the surface of the nano-lipidemulsion (as opposed to it being entrapped in other mRNA vaccines using NLPs), thereby easing manufacturability and minimizing losses.

4.7 Vaxzevria :

1. Country :

Developed in the United Kingdom by Oxford University and British-Swedish company AstraZeneca, using as a vector the modified chimpanzee adenovirus ChAdOx1.

2. Content :

Vaxzevria is made up of another virus (of the adenovirus family) that hasbeen modified to contain the gene for making a protein from SARS-CoV-2, the virus that causes COVID-19.This is a multidose vial which contains 10 doses of 0.5 ml (see section6.5).One dose (0.5 ml) contains: Chimpanzee Adenovirus encoding the SARS-CoV-2 Spike glycoprotein (ChAdOx1-S), not less than 2.5 × 108 infectious units (Inf.U) Produced in genetically modified human embryonic kidney (HEK) 293cells and by recombinant DNA technology. This product contains genetically modified organisms (GMOs).Excipient with known effect Each dose (0.5 ml) contains approximately 2 mg of ethanol.[59]

3. Ingredients they contain :

The active ingredients in Vaxzevria vaccine is COVID 19 vaccine (ChAdOx1s[recombinant])[69]. The ingredients vaccine consists of L-histidine, L-histidine hydrochloride monohydrate, Magnesium chloride, Hexahydrate polysorbate 80 (E443) ethanol, sucrose, sodium chloride, disodium edetate dehydrate.[60]

4. Adverse drug reaction :

The patient may suffer from injection site tenderness, headache, the sitaution like fatigue may be observed in some cases, myalgia, malise and pyrexia can be observed. The patient may suffer from Chills, [61][62]

5. Storage/shelf life :

Opened vial -

Chemical and physical in-use stability have been demonstrated for 6 hours when stored at temperatures up to 30°C and for 48 hours when stored in a refrigerator (2°C – 8°C). After this time, the vial must be discarded. Do not return it to the refrigerator after storage outside the refrigerator. Alternatively, an opened vial may be stored in a refrigerator (2°C –8°C) for a maximum of 48 hours if it is immediately returned to the refrigerator following each puncture. From a microbiological point of view, after first opening the vaccine should be used immediately. If the vaccine is not used immediately, in-use storage times and conditions are the responsibility of the user.[62]

6. Special precautions for storage :-

Store in a refrigerator (2°C – 8°C).Do not freeze. Keep vials in outer carton in order to protect from light[64]

7. Medical uses :

The Oxford–AstraZeneca COVID?19 vaccine is used to provide protection against infectionby the SARS- CoV-2 virus in order to prevent COVID-19 in adults aged 18 years and older.[65] The medicine is administered by two 0.5 ml (0.017 US fl oz) doses given by intramuscular injection into the deltoid muscle (upper arm). The initial course consists of two doses with an interval of 4 to 12 weeks between doses. The World Health Organization (WHO) recommends an interval of 8 to 12 weeks between doses for optimal efficacy.[66] As of August 2021, there is no evidence that a third booster dose is needed to prevent severe disease in healthy adults.[66][67]

8.Contraindications :

The Oxford–AstraZeneca COVID-19 vaccine should not be administered to people who have had capillary leak syndrome.[68][69]

• Sumarry Table:-

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