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Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) 1 NAME OF THE MEDICINAL PRODUCT GEMCOVAC™-19 Lyophilized mRNA vaccine for Injection (COVID-19) 50μg/5dose and 200μg/20 dose vial. Lyophilized mRNA Vaccine for Injection (COVID-19) 10μg/dose, Presentation: 5 & 20 dose/vial 2 QUANTITATIVE AND QUALITATIVE COMPOSITION Active Pharmacopoeial Quantity/ Vial of Quantity/ Vial of Sr. No. Name of Ingredient Quantity/ Dose Monograph 5 dose 20 dose 1 mRNA (In-vitro In House 10 µg 50 µg 200 µg transcribed self amplifying mRNA encoding for the S- protein of SARS-CoV-2) Inactive Name of Pharmacopoeial Quantity/ Quantity/ Quantity/ Vial Sr. No. Ingredient Monograph Dose Vial of 5 dose of 20 dose 1 DOTAP In House 0.30 mg 1.50 mg 6.00 mg 2 Squalene BP/ Ph.Eur 0.376 mg 1.88 mg 7.52 mg 3 Sorbitan BP/ Ph.Eur 0.372 mg 1.86 mg 7.44 mg Monostearate 4 Polysorbate 80 I.P./BP/Ph.Eur./USP 0.372 mg 1.86 mg 7.44 mg 5 Sucrose I.P./BP/Ph.Eur. 50.00 mg 250.00 mg 1000.00 mg 6 Citric Acid I.P./BP/Ph.Eur./IH 1.05 mg 5.25 mg 21.00 mg Monohydrate 3 PHARMACEUTICAL FORM GEMCOVAC™-19 is a Lyophilized powder that needs to be reconstituted with Sterile Water for Injections before administration. The reconstituted solution is off white liquid free from any visible particles.Each dose of 0.5 mL contains 10 μg of GEMCOVAC™-19 mRNA vaccine.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial 4 CLINICAL PARTICULARS 4.1 Therapeutic Indications GEMCOVAC™-19 is indicated for active immunization of individuals ≥18 years old for the prevention of COVID-19. 4.2 Posology and method of administration Posology GEMCOVAC™-19 should be administered in two doses, second dose after 28 days of the first dose. A volume of 0.5 ml should be administered intramuscularly. It is recommended that individuals who receive a first dose complete the vaccination course with GEMCOVAC™-19. Interchangeability There is no safety, immunogenicity or efficacy data to support interchangeability of GEMCOVAC™- 19 with any other COVID-19 vaccines. Special Populations Elderly population: No dose adjustment is required for the elderly population. Pediatric population: The safety and efficacy of GEMCOVAC™-19 has not been established in children and adolescents < 18 years of age. 4.3 Contraindications Hypersensitivity to any constituents of GEMCOVAC™-19. Individuals below 18 years of age. 4.4 Special warnings and precautions for use  GEMCOVAC™-19 should not be administered intravenously, intradermally or subcutaneously.  Hypersensitivity and Anaphylaxis: There is a risk of hypersensitivity reactions due to the constituents of GEMCOVAC™-19. Supervision and if needed the appropriate medical treatment should be provided to all the vaccine recipients after immunization.  Concurrent Illness: As with other vaccines, administration of GEMCOVAC™-19 should be postponed in individuals suffering from an acute severe febrile illness.  Risk of bleeding with intramuscular administration: As with other intramuscular injections, GEMCOVAC™-19 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.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial  Immunocompromised Individuals: It is not known whether individuals with impaired immune responsiveness, including individuals receiving immunosuppressant therapy, will elicit the same response as immunocompetent individuals to the vaccine regimen.  Anxiety related reactions: Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting.  Interchangeability: There are no safety, immunogenicity or efficacy data to support interchangeability of GEMCOVAC™-19 with any other COVID-19 vaccines.  Reconstitution: GEMCOVAC™-19 is available as a lyophilized powder which needs to be reconstituted with Sterile Water for Injection. Draw 3 ml / 11 ml of water and reconstitute the 5 / 20 dose vial respectively. Gently swirl the vial intermittently for approximately 120 seconds till all the lyophilized contents are dissolved and no particles are visible. The solution should be off white liquid free from any visible particles. Inject IM 0.5 mL of the reconstituted vaccine solution within 6 hours of reconstitution to the recipient. If not administered within 30 minutes after reconstitution, keep reconstituted vaccine back at +2 ºC to +8 ºC. This vaccine is multi- dose. It will be used for dosing up to 5 recipients who must be dosed on same day within 6 hours of reconstitution. 4.5 Interaction with other medicinal products and other forms of Interaction The safety, immunogenicity and efficacy of co-administration of GEMCOVAC™-19 with other vaccines or medications have not been evaluated. 4.6 Pregnancy and lactation Safety, efficacy and immunogenicity have not been established in pregnant women and nursing mothers. It is unknown if GEMCOVAC™-19 is excreted in human milk. 4.7 Effects on ability to drive and use machines No studies on the effect of GEMCOVAC™-19 on the ability to drive or use machines have been performed. 4.8 Undesirable Effects 4.8.1 Safety data from Phase I Clinical Trial The Phase I clinical trial was conducted in 82 healthy subjects between the age of 18 and 70 years. Three dose strengths of 5 µg, 10 µg and 25 µg were compared with placebo. The primary endpoint of this study was to assess the safety, reactogenicity and tolerability of GEMCOVAC™-19 at the threeLyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial dose strengths following 2 doses administered 28 days apart. Local Solicited Adverse Event: There was no significant difference among the three dose strengths. The most frequent local adverse event was injection site pain, followed by induration/swelling and erythema/redness. Most of the solicited local AEs were of Grade 1 intensity. No immediate solicited AEs or solicited AEs of Grade 3 and above intensity were reported. Systemic Solicited Adverse Event: The occurrence of systemic solicited adverse events was comparable between all dose strengths. Fatigue was most commonly reported, followed by headache and fever. Myalgia and chills were reported in less than 30% of the participants. Most of the solicited systemic AEs were of Grade 1 intensity. None of the adverse events were of Grade 3 and above as per the DAIDs criteria. Unsolicited Adverse Events: All adverse events except 5 were considered not related. The related adverse events were laboratory abnormalities which resolved completely. Most of the unsolicited AEs were of Grade 1 severity. No Grade 3 or higher adverse event was observed in participants receiving GEMCOVAC™-19. None of the adverse events led to death. Serious Adverse Events: No related serious adverse events were observed in this study. 4.8.2 Safety data from Phase II Clinical Trial The Phase II clinical trial was conducted in 415 participants. The safety and immunogenicity of GEMCOVAC™-19 was compared with the approved vaccine COVISHIELD™. The participants were randomized to the two arms in a 1:1 ratio. Table 1. Phase II clinical trial demography Demography GEMCOVAC™-19 COVISHIELD™ (n = 207) (n = 208) Age [Median (min., max.)] 33.0 (18, 74) 34.0 (18, 69) Male/Female [n] 137/70 138/70 Weight [Mean (SD)] 62.6 (12.82) 60.9 (10.22) BMI [Mean (SD)] 23.75 (4.37) 23.29 (3.99) Co-morbid Conditions Anemia [n (%)] 3 (1.4) 4 (1.9) Hypothyroidism [n (%)] 0 1 (0.5) Diabetes Mellitus [n (%)] 3 (1.4) 3 (1.4) Asthma [n (%)] 0 1 (0.5) Hypertension [n (%)] 0 1 (0.5)Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial Local Solicited Adverse Events: A total of 107 participants (51.7%) receiving GEMCOVAC™- 19 experienced at least one solicited local adverse event compared to 79 participants (38.0%) in the COVISHIELD™ arm at any dose. However, this difference was restricted to Grade 1 and 2 intensities. The Grade 3 and above adverse events were comparable between the two vaccine arms. In participants receiving GEMCOVAC™-19, pain at injection site was the most commonly observed event (47.3% of participants), followed by warmth (16.4% of participants), swelling/induration (9.2% of participants), erythema (2.4% of participants), pruritus (1.9% of participants) and bruising (0.5% of participants). Systemic Solicited Adverse Events: A total of 100 participants (48.3%) receiving GEMCOVAC™-19 experienced at least one solicited systemic adverse event compared to 93 participants (44.7%) in the COVISHIELD™ arm at any dose. In the participants who received GEMCOVAC™-19, headache was most commonly observed (28.0% of participants), followed by fatigue (27.1% of participants), fever (23.7% of participants), myalgia (22.2% of participants), chills (17.4 % of participants), malaise (12.6% of participants), arthralgia (12.1% of participants) and nausea (6.3% of participants). Most of the solicited systemic adverse events were of Grade 1 intensity. Four subjects (1.9%) in the GEMCOVAC™-19 arm and 3 (1.4%) in the COVISHIELD™ arm reported solicited adverse events of Grade 3. One subject (0.5%) in the GEMCOVAC™-19 arm and 2 (1.0%) in the COVISHIELD™ arm reported solicited adverse event of Fever of Grade 4 intensity. Unsolicited Adverse Events: A total of 20 participants (9.7%) in the GEMCOVAC™-19 arm and 25 participants (12.0%) in the COVISHIELD™ arm observed at least 1 unsolicited event following any vaccination. Of these adverse events, 5 in the GEMCOVAC™-19 arm were termed vaccine related (2 incidences of chest pain, 1 incidence of injection site pain, 1 incidence of dizziness and 1 incidence of urticaria). Serious Adverse Events: A total of 8 serious adverse events were reported out of which 1 was fatal and related to COVISHIELD™ (Pulmonary Embolism). Other adverse events were termed not related to vaccine. 4.8.3 Safety data from Phase III Clinical Trial The Phase III clinical trial was conducted in 4000 participants who were randomized to receive GEMCOVAC™-19 or COVISHIELD™ in a 3:1 ratio.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial Table 2. Phase III clinical trial demography Demography GEMCOVAC™-19 COVISHIELD™ (n = 2992) (n = 998) Age [Median (min., max.)] 33.0 (18, 81) 33.0 (18, 79) Male/Female [n] 2348/644 781/217 Weight [Mean (SD)] 61.2 (11.30) 61.3 (11.20) BMI [Mean (SD)] 22.46 (3.78) 22.53 (3.90) Co-morbid Conditions Hypertension 13 (0.4) 2 (0.2) History of hysterectomy [n (%)] 9 (0.3) 1 (0.1) Hypothyroidism [n (%)] 4 (0.1) 0 Diabetes Mellitus [n (%)] 10 (0.3) 0 Uterine leiomyoma [n (%)] 1 (0) 0 Asthma [n (%)] 1 (0) 0 Local Solicited Adverse Events: A total of 928 (31.0%) of the participants receiving GEMCOVAC™- 19 and 263 (26.4%) of the participants receiving COVISHIELD™ experienced at least one local solicited adverse event. In the participants receiving GEMCOVAC™-19, pain at the injection site was the most common local solicited reaction (27.5% of participants), followed by swelling at injection site (3.6% of participants), warmth at injection site (3.1% of the participants), redness at injection site (1.7% of participants), pruritus (0.4% of the participants) and bruising (0.1% of participants). None of the adverse events were above Grade 2. Systemic Solicited Adverse Events: A total of 955 (31.9%) participants receiving GEMCOVAC™-19 and 340 (34.1%) participants receiving COVISHIELD™ observed at least 1 systemic solicited adverse event. In participants receiving GEMCOVAC™-19, the most common systemic solicited event was fever (15.6% of participants) followed by headache (12.9% of participants), fatigue (7.2% of participants), myalgia (6.9% of participants), chills (4.9% of participants), malaise (1.7% of participants), arthralgia (1.3% of participants) and nausea (1.3% of participants). Vomiting and influenza like illness was seen in < 1% of participants. Unsolicited Adverse Events: A total of 51 (1.7%) participants receiving GEMCOVAC™-19 and 15 (1.5%) of participants receiving COVISHIELD™ observed at least one unsolicited adverse event. In the GEMCOVAC™-19 arm, the 4 events were considered related to the vaccine (chestLyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial pain, uterine haemorrhage, angioedema and pruritus). Serious Adverse Events: A total of 10 serious adverse events (7 in GEMCOVAC™-19 and 3 in COVISHIELD™) were observed. Of these, 1 serious adverse event was possibly related to GEMCOVAC™-19 (Abnormal Uterine Bleeding) and 1 serious adverse event was related to COVISHIELD™ (Fever). Adverse drug reactions observed during the clinical trials were ranked using the following conventions: Very Common : ≥ 1/10 Common : ≥ 1/100 to < 1/10 Uncommon : ≥ 1/1000 to < 1/100 Rare : ≥ 1/10000 to < 1/1000 Table 3. Adverse Events Observed in Phase III trial with GEMCOVAC™-19 MedDRA System Organ Class Frequency Adverse Event General Disorders and Administration Site Very Common Pain/Tenderness, Fever Conditions Common Redness/Erythema, Swelling/Induration, Warmth, Chills, Malaise, Fatigue Uncommon Pruritus, Bruising Musculoskeletal and connective tissue disorders Common Myalgia, Arthralgia Nervous System Disorders Very Common Headache Gastrointestinal Disorders Common Nausea Uncommon Vomiting Respiratory, thoracic and mediastinal disorders Uncommon Influenza like illness No cases of myocarditis/pericarditis (Adverse Event of Special Interest) were reported in Phase I, II and III clinical trial. 4.9 Overdose There is no data on overdose of GEMCOVAC™-19.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial 5 PHARMACOLOGICAL PARTICULARS 5.1 Pharmacodynamic Properties 5.1.1 Pre-clinical Immunogenicity Immunogenicity studies were conducted with GEMCOVAC™-19 in mice, rats and hamsters. The vaccine elicited robust humoral (binding and neutralizing antibodies), immune responses to the Spike antigen in different animal models. Animal Challenge Study GEMCOVAC™-19 efficacy in the prevention of SARS-CoV-2 infection was evaluated in virus challenge study conducted in Syrian Golden Hamsters. The results indicated that intramuscular administration of GEMCOVAC™-19 elicited immune responses that mitigated SARS-CoV-2 virus replication and pathogenesis significantly. The reduced viral replication and presence of SARS-CoV- 2 neutralizing antibodies coincided with the reduced clinical signs and lung tissue pathology in vaccinated animals compared with the infected-unvaccinated groups. 5.1.2 Immunogenicity from Phase I Clinical Trial A dose-ranging (5 µg, 10 µg and 25 µg), placebo-controlled, Phase I study was conducted in 82 health individuals between 18-70 years of age. Anti-Spike IgG antibodies: There was a statistically significant rise in the anti-S- IgG GMT at Day 57 compared to baseline (Day 1) in the 5 µg, 10 µg and 25 µg. The GMT at Day 57 were 6408 (95% CI: 2330 – 17624) for the 5 µg group, 17013 (95% CI: 7115 – 40682) for the 10 µg group, 16266 (95% CI: 5777 – 45801) for the 25 µg group and 781 (95% CI: 397 – 1535) in the placebo group. cPASS Neutralization Assay: The cPass SARS-CoV-2 Surrogate Neutralization Antibody assay (Genscript) measures the neutralizing antibodies in blood sera of the participants. Sera collected from participants at Day 57 showed a high neutralization capacity of 97%, 96% and 93% for the 5 µg, 10 µg and 25 µg groups respectively. 5.1.3 Immunogenicity from Phase II Clinical Trial In Phase II, the immunogenicity of GEMCOVAC™-19 was compared with that of COVISHIELD™ at Day 43. Anti-Spike IgG Antibody: At Day 43, the IgG GMT was 216320 (95% CI: 178561 - 262063) in the COVISHIELD™ arm and 282464 (95% CI: 233994 - 340974) in the GEMCOVAC™-19 arm. The Least Square Geometric Mean Ratio (GEMCOVAC™-19: COVISHIELD™) was 1.267 and there was no statistically significant difference between the two.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial PRNT Assay: Plaque reduction neutralization test (PRNT) analysis was performed in a subset 50 of the population in the two groups. At Day 43, the PRNT GMT were 1085 (95% CI: 718 – 50 1639) in the COVISHIELD™ arm and 802 (95% CI: 420 – 1532) in the GEMCOVAC™-19 arm. There was no statistically significant difference in the PRNT GMT at day 43 in the two 50 groups. cPASS Neutralization Assay: At Day 43, the neutralization capacity was at 93.3% (SD: 9.99) in the COVISHIELD™ arm and 86.9% (SD: 24.61) in the GEMCOVAC™-19 arm. There was no statistically significant difference between the two groups at Day 43. Seroconversion: Seroconversion rate assessed by a ≥ 2-fold rise in anti-spike IgG titer in seropositive subjects and ≥ 4-fold rise in anti-spike IgG titre in seronegative subjects at Day 43 was similar in both the groups (91.2% in GEMCOVAC™-19 and 93.7% in COVISHIELD™). Cellular Immune Response: T-cell responses against the spike protein were assessed by using flow- cytometry based intracellular cytokine–staining (ICS) assay, performed on peripheral blood mononuclear cells (PBMCs). Both COVISHIELD™ and GEMCOVAC™-19 cohorts showed maximum spike peptides stimulated IFNγ expression in CD4+ T-Cell at day-29. COVISHIELD™ cohort showed relatively higher IFNγ expressions in CD4+ T-cells, whereas GEMCOVAC™-19 generated relatively higher spike stimulated IL-2 expressions in CD4+ T- Cells. Both COVISHIELD™ as well as GEMCOVAC™-19 showed similar TNFα expressions in both CD4+ and CD8+ T-cells. Th2 cytokines (IL-4 and IL-13) expressions were very minimal or undetectable in both the vaccinated cohorts. 5.1.4 Immunogenicity from Phase III Clinical Trial In Phase III, the immunogenicity of GEMCOVAC™-19 was compared to that of COVISHIELD™ at Day 43 in 714 subjects. Anti-Spike IgG Antibodies: Anti-Spike IgG antibodies were compared in a total of 714 participants of which 237 received COVISHIELD™ and 477 received GEMCOVAC™-19. There was a statistically significant rise in antibodies in both groups from baseline to Day 43. The GMT of GEMCOVAC™- 19 was found to be non-inferior to COVISHIELD™.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial Table 4. Anti-spike IgG antibodies in Phase III study Time Point GEMCOVAC™-19 COVISHIELD™ (n = 477) (n = 237) Baseline at Day 1 11647.8 10200.0 (9956.4 - 13626.6) (8018.9 - 12974.4) [GMT(95% CI)] Day 43 339930.2 319605.1 (311391.4 - 371084.5) (281630.1 - 362700.6) [GMT(95% CI)] The anti-Spike IgG antibodies were also analyzed in 3 groups stratified by age (18 - ≤ 40, > 40 - ≤ 60 and > 60 years). There was no reduction in the Anti-Spike IgG titer at Day 43 with GEMCOVAC™-19 and no dose adjustment is required for older age groups more than 60 years of age. Table 5. Anti-Spike IgG Antibodies at Day 43 in participants receiving GEMCOVAC™-19 stratified by age Day/Age 18 - ≤ 40 years > 40 - ≤ 60 years > 60 years (n = 349) (n = 114) (n = 14) Day 43 322099.8 369352.3 662433.1 (290152.0 -357565.2) (311528.3 - 437909.4) (441229.4 - 994533.8) [GMT(95% CI)] PRNT Assay: PRNT50 analysis performed using the D614G variant of SARS-CoV-2 in 76 50 participants. There was a substantial increase in the neutralizing antibodies in both the arms from baseline till Day 43. Neutralizing antibody GMT of GEMCOVAC™-19 was found to be comparable to COVISHIELD™.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial Table 6. Neutralization by PRNT assay against D614G variant of SARS-CoV-2 in Phase III 50 study Time Point GEMCOVAC™-19 COVISHIELD™ (n = 51) (n = 25) Baseline at Day 1 29.3 (16.7 - 51.6) 31.1 (13.6 - 70.9) [GMT(95% CI)] Day 43 1099.9 (817.9 – 1479.2) 841.6 (461.5 – 1534.8) [GMT (95% CI)] cPASS Neutralization Assay: cPASS was performed in all 714 participants of the immunogenicity cohort. There was a statistically significant rise in the neutralizing antibodies in both the groups from baseline to Day 43. The percent neutralization was comparable in both groups at Day 43. Table 7. Neutralization by cPASS assay in Phase III study Time Point GEMCOVAC™-19 COVISHIELD™ (n = 477) (n = 237) Baseline at Day 1 [% (SD)] 44.8 (33.75) 44.5 (34.40) Day 43 [% (SD)] 94.8 (5.74) 93.9 (7.59) Neutralization by cPASS was also assessed in 3 groups stratified by age (18 - ≤ 40, > 40 - ≤ 60 and > 60 years). The neutralization was > 90% in all the groups at Day 43 indicating a high protection against SARS-CoV-2 with GEMCOVAC™-19. Table 8. Neutralization by surrogate virus assay (cPASS) at Day 43 in participants receiving GEMCOVAC™-19 stratified by age Day/Age 18 - ≤ 40 years > 40 - ≤ 60 years > 60 years (n = 349) (n = 114) (n = 14) Day 43 [% (SD)] 94.5 (6.38) 95.5 (3.44) 96.7 (0.51) Pseudovirus Neutralization Assay: The neutralization using pseudovirus assay was conducted in 40 participants of the immunogenicity cohort. A statistically significant rise in the GMT was observed at Day 43 compared to the baselines. The GMT at Day 43 were comparable in both theLyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial groups. Table 9. Neutralization using pseudovirus assay in Phase III study Time Point GEMCOVAC™-19 COVISHIELD™ (n = 27) (n = 13) Baseline at Day 1 14.7 (7.7 – 27.9) 10.9 (4.2 – 27.8) [GMT (95% CI)] Day 43 323.6 (160.3 – 653.0) 384.4 (142.8 – 1034.7) [GMT (95% CI)] Seroconversion: Seroconversion rate assessed by a ≥ 2-fold rise in anti-spike IgG titer in seropositive subjects and ≥ 4-fold rise in anti-spike IgG titer in seronegative subjects at Day 43 was similar in both the groups (94.1% in GEMCOVAC™-19 and 91.1% in COVISHIELD™). GEMCOVAC™-19 was found to be non-inferior to COVISHIELD™. Cellular Response: Cellular response was assessed in 122 subjects of the immunogenicity cohort. Both COVISHIELD™ and GEMCOVAC™-19 cohorts elicited vigorous spike-specific T-cell responses. These responses were biased towards T helper 1 cell (Th1) cytokines (IFNγ and TNFα) expression. Th2 cytokines (IL-4 and IL-13) expressions were very minimal or undetectable in both the vaccinated cohorts. Additionally, COVISHIELD™ and GEMCOVAC™-19 cohorts showed spike-specific poly- functional T-Cell responses. Both the vaccines showed elevated spike-specific memory B-Cell populations as compared to their respective baseline. 5.2 Pharmacokinetic properties Evaluation of Pharmacokinetic properties is not required for Vaccine 5.3 Preclinical safety data A GLP- compliant repeat dose toxicity study was conducted in wistar rats. A dose of 25 µg / 0.5 ml was administered once in 2 weeks over a period of 4 weeks (days 1, 15 and 29) along with control. GEMCOVAC™-19 administered intramuscularly was well tolerated by the rats. Treatment with GEMCOVAC™-19 did not cause any remarkable or adverse effects on the absolute and relative (% of body weight) values of weights of liver, kidneys, adrenals, testes / uterus (with cervix), brain, lungs and heart of the rats in this study. The necropsy examination of all rats conducted at termination of the study did not reveal any incidence of treatment related systemic pathology. No mortality occurred during the duration of the study. GEMCOVAC™-19 was found to be safe, immunogenic and well tolerated at the sites of injections.Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial 6 PHARMACEUTICAL PARTICULARS 6.1 List of Excipients DOTAP Squalene Sorbitan Monostearate Polysorbate 80 Sucrose Citric Acid Monohydrate 6.2 Incompatibilities In the absence of incompatibility studies, the vaccine should not be mixed with any other medicinal products. 6.3 Shelf life The expiry date of lyophilized vaccine is indicated on the label and outer pack. Once reconstituted, the solution can be considered stable up to 6 hours when stored at +2ºC to +8ºC without opening flip-off seal and rubber stopper. All reconstituted multi-dose vials of GEMCOVAC™-19 should be discarded at the end of immunization session or within six hours whichever comes first. 6.4 Special precautions for storage Store in a refrigerator (+2ºC to +8ºC). Do not freeze or shake the reconstituted solution. 6.5 Nature and contents of container GEMCOVAC™-19 is presented in USP type I glass vial with Bromobutyl stopper and Flip- off Aluminium seal. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7 MARKETING AUTHORIZATION PREQUALIFICATION HOLDER Gennova Biopharmaceuticals Limited, Block 1, Plot No. P-1 & P-2, ITBT Park, Phase II, MIDC, Hinjawadi, Pune-411057Lyophilized mRNA vaccine for Injection (COVID-19) Presentation: 5 & 20 dose/vial 8 MARKETING AUTHORIZATION NUMBER(S) PD/Vacc-06 9 DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION MF/BIO/22/000064 dated 28-JUN-2022 10 DATE OF REVISION OF THE TEXT 2nd July 2022.055 Y U V I 20GR6AP2HIC2 GEMCOVAC-19 Injection Same Size Fact Sheet (Both Side Open) Actual Size : L. 90 x H. 240 mm Folded : 90 x 30 mm Date : 27.05.2022 (Proof) Date : 01.06.2022 (Proof) Date : 20.06.2022 (Proof) Fact. : Packaging (Mr. Shrikant Pandit) mm 042 mm 042 90 mm 90 mm Manufactured and Marketed by: Gennova Biopharmaceuticals Limited Block 1, Plot No. P-1 & P-2, I.T.B.T. Park, Phase II, MIDC, Hinjawadi, Pune - 411 057, India. TM Trade Mark Owned by Gennova Biopharmaceuticals Ltd. 2202 enuJ ht02 : noisiver fo etaD 20NI315020015 FACT SHEET FOR VACCINE RECIPIENTS & CAREGIVERS WHAT IF YOU MISSED YOUR SECOND DOSE? RESTRICTED USE IN EMERGENCY SITUATION OF COVID-19 If you forget to get the second dose at the scheduled time, ask your healthcare provider / doctor for advice. It is important that you return for your second dose TM of GEMCOVACTM-19 vaccine. GEMC VAC-19 HAS THE GEMCOVACTM-19 VACCINE BEEN USED BEFORE? The GEMCOVACTM-19 has been used in Phase I, II and III clinical trials, a number of participants received one or two doses in Indian trials. IN PREVENTION OF COVID-19 DISEASE Approximately, 3250 individuals have received 2 doses of GEMCOVACTM-19. IN INDIVIDUALS 18 YEARS OF AGE AND OLDER WHAT ARE THE BENEFITS OF THE GEMCOVACTM-19 VACCINE? In an ongoing Phase-II / III clinical trial, GEMCOVACTM-19 has been shown to The Gennova Biopharmaceuticals COVID-19 Vaccine (GEMCOVACTM-19) generate protective immune responses. GEMCOVACTM-19 generates anti- is administered to prevent Coronavirus Disease 2019 (COVID-19) caused Spike-IgG and neutralising antibodies. However, it is important to note that by SARS-CoV-2. This Fact Sheet contains information to help you GEMCOVACTM-19 may not protect everyone who is vaccinated for understand the risks and benefits of the Gennova Biopharmaceuticals COVID-19. The duration of protection against COVID-19 is currently COVID-19 Vaccine (GEMCOVACTM-19). unknown. REPORTING OF SIDE EFFECTS WHAT ARE THE RISKS OF THE VACCINE? As with any new medicine, this vaccine will be closely monitored to allow Side Effects that have been reported with GEMCOVACTM-19 include: quick identification of any new safety information. You can help by reporting Very Common (may affect more than 1 in 10 people) any side effects you may get after vaccination to Gennova • Injection site pain Biopharmaceuticals Limited, who is the manufacturer of GEMCOVACTM-19 • Fever vaccine at Safety@gennova.co.in For more information, please read this • Headache Information Sheet carefully. Common (may affect up to 1 in 10 people) You are being offered the Gennova Biopharmaceuticals Limited • Redness/Erythema GEMCOVACTM-19 Vaccine to prevent COVID-19 caused by SARS-CoV-2. • Swelling/Induration This Fact Sheet contains information to help you understand the risks and • Warmth benefits of the GEMCOVACTM-19 Vaccine, which you may receive. Talk to the • Chills healthcare provider / doctor if you have questions. • Malaise The GEMCOVACTM-19 is a vaccine and may prevent you from getting • Fatigue COVID-19 disease. GEMCOVACTM-19 may not protect everyone. • Myalgia The GEMCOVACTM-19 vaccination course consists of two separate doses of • Arthralgia 0.5 ml each administered 4-weeks apart. • Nausea For intramuscular (IM) injection only. Uncommon (may affect up to 1 in 100 people) WHAT YOU NEED TO KNOW BEFORE YOU GET THIS VACCINE • Pruritus WHAT IS COVID-19? • Bruising COVID-19 is an infectious disease caused by a coronavirus called SARS- • Vomiting CoV-2. You can get COVID-19 by coming in contact with an infected person. It • Influenza like illness predominantly causes a respiratory illness that can affect other organ A severe allergic reaction may very rarely occur after getting a dose of systems. People with COVID-19 have reported a wide range of symptoms, GEMCOVACTM-19. These may not be all the possible side effects of ranging from mild to severe illness. Symptoms may appear 2 to 14 days after GEMCOVACTM-19. Serious and unexpected side effects may occur. exposure to the virus. Symptoms may include: fever or chills; cough; GEMCOVACTM-19 is still being studied in clinical trials. shortness of breath or difficulty in breathing; fatigue; muscle or body aches; WHAT SHOULD I DO ABOUT SIDE EFFECTS? headache; new loss of taste or smell; sore throat; congestion or runny nose; If you experience any side effect(s), please contact / visit your health provider nausea or vomiting; diarrhoea. / Vaccinator / Officer supervising your vaccination or immediately go to the WHAT IS THE GENNOVA BIOPHARMACEUTICAL COVID-19 VACCINE nearest hospital. In addition, you can report side effects after vaccination to (GEMCOVACTM-19)? Gennova Biopharmaceuticals Limited, who is the manufacturer of GEMCOVACTM-19 is a mRNA-based vaccine using Spike (S)-protein of the GEMCOVACTM-19 vaccine at Safety@gennova.co.in virus as antigen. GEMCOVACTM-19 is approved for restricted use in WHAT IF I DECIDE NOT TO GET GEMCOVACTM-19? emergency situation that may prevent COVID-19. The vaccine is available as It is your choice to receive or not receive GEMCOVACTM-19. Should you a lyophilized powder. decide not to receive the GEMCOVACTM-19, it will not change your standard WHAT SHOULD YOU MENTION TO YOUR HEALTHCARE PROVIDER / medical care. DOCTOR BEFORE YOU GET GEMCOVACTM-19 VACCINE? CAN I RECEIVE GEMCOVACTM-19 WITH OTHER VACCINES? Tell the healthcare provider/doctor about all your medical conditions There is no scientific information yet available on the appropriateness of use including: of GEMCOVACTM-19 along with other vaccines. • If you have ever had a severe allergic reaction (anaphylaxis) after any drug, food, any vaccine or any ingredients of GEMCOVACTM-19 vaccine WHAT IF I AM PREGNANT? Safety, efficacy and immunogenicity have not been established in pregnant • If you have fever women and nursing mothers. It is unknown if GEMCOVACTM-19 is excreted in • If you have a problem with bleeding or bruising, or if you are taking a blood human milk. There is currently insufficient information to inform about the thinning medicine (anticoagulant) associated risks in pregnancy. • If you are immunocompromised or are on a medicine that affects your immune system WHAT IF I HAVE ALLERGIES? • If you are pregnant or plan to become pregnant Individuals who have a known severe allergy to any component of • If you are breastfeeding GEMCOVACTM-19 are NOT advised to be vaccinated. Individuals with a • If you have received another COVID-19 vaccine history of allergies to oral medications or a family history of allergic reactions, or who might have a mild allergy to vaccines (but no anaphylaxis) may still get WHO SHOULD GET GEMCOVACTM-19 VACCINE? vaccinated. GEMCOVACTM-19 Vaccine has been approved for restricted use in WHAT IF I AM IMMUNOCOMPROMISED? emergency situation in individuals 18 years of age and older. It is not known whether individuals with impaired immune responsiveness, WHO SHOULD NOT GET GEMCOVACTM-19 VACCINE? including individuals receiving immunosuppressant therapy, will elicit the You should not get GEMCOVACTM-19 if you: same response as immunocompetent individuals to the vaccine regimen. • Had a severe allergic reaction to any ingredients of the vaccine WILL THE GENNOVA BIOPHARMACEUTICAL COVID-19 VACCINE • Had a severe allergic reaction after a previous dose of this vaccine (GEMCOVACTM-19) GIVE ME COVID-19? • Currently have an acute infection or fever No. GEMCOVACTM-19 is an mRNA-based vaccine and doesn't contain WHAT ARE THE INGREDIENTS IN THE GEMCOVACTM-19? SARS-CoV-2. There are no chances of getting COVID-19. One dose of 0.5 ml contains the mRNA 10 µg, DOTAP 0.3 mg, Squalene HOW CAN I LEARN MORE? 0.376 mg, Sorbitan Monostearate 0.372 mg, Polysorbate-80 0.372 mg, Citric • Ask the vaccination provider/ doctor. acid monohydrate 1.05 mg and Sucrose 50 mg. • Contact your local/ state or central health department. HOW IS THE GEMCOVACTM-19 GIVEN? GEMCOVACTM-19 will be given to you as an intramuscular (IM) injection only, preferably in the deltoid muscle. The GEMCOVACTM-19 vaccination course consists of two separate doses of 0.5 ml each. If you receive one dose of the GEMCOVACTM-19 vaccine, then the second dose should be administered 4 weeks after the first dose.Y U V I 8G7RA2PH2IC GEMCOVAC-19 Injection (5/20 Dose) Same Size Pack Insert (Both Side Open) Actual Size : L. 180 x H. 420 mm Folded : 90 x 43 mm Date : 01.06.2022 (Proof) Date : 07.06.2022 (Proof) Date : 20.06.2022 (Proof) Date : 21.06.2022 (Proof) Date : 27.06.2022 (Proof) Date : 02.07.2022 (Proof) Date : 04.07.2022 (Proof) Date : 07.07.2022 (Proof) Date : 08.07.2022 (Proof) Fact. : Packaging (Mr. Shrikant Pandit) mm 024 180 mm Neutralization by cPASS was also assessed in 3 groups stratified by age For the Use Only of a Registered Medical Practitioner or a Hospital or a Laboratory (18 - ≤ 40, > 40 - ≤ 60 and > 60 years). The neutralization was > 90% in all RESTRICTED USE IN EMERGENCY SITUATION OF COVID-19 the groups at Day 43 indicating a high protection against SARS-CoV-2 with GEMCOVAC™-19. Lyophilized mRNA Vaccine for Injection (COVID-19) Table 8. Neutralization by surrogate virus assay (cPASS) at Day 43 in participants receiving GEMCOVAC™-19 stratified by age 50 μg/5 Dose and 200 μg/20 Dose Vial TM GEMC VAC-19 Pseudovirus Neutralization Assay: The neutralizing antibodies using pseudovirus assay were evaluated in 40 participants of the 1. GENERIC NAME immunogenicity cohort. A statistically significant rise in the GMT was GEMCOVAC™-19, lyophilized powder for injection observed at Day 43 compared to the baselines. The GMT at Day 43 were 2. QUALITATIVE AND QUANTITATIVE COMPOSITION comparable between the two groups. One dose of 0.5 ml contains: Table 9. Neutralization using pseudovirus in Phase III study mRNA (In-vitro transcribed self amplifying mRNA encoding for the S-protein of SARS-CoV-2)10.00 μg DOTAP 0.30 mg Squalene 0.376 mg Sorbitan Monostearate 0.372 mg Polysorbate 80 0.372 mg Citric Acid Monohydrate 1.05 mg Sucrose 50.00 mg Seroconversion: Seroconversion rate assessed by a ≥ 2-fold rise in anti- 3. DOSAGE FORM AND STRENGTH Spike IgG titer in seropositive subjects and ≥ 4-fold rise in anti-spike IgG GEMCOVAC™-19 is a lyophilized powder that needs to be reconstituted titer in seronegative subjects at Day 43 was similar in both the groups with Sterile Water for Injections I.P. before administration. The (94.1 % in GEMCOVAC™-19 and 91.1% in COVISHIELD™). reconstituted solution is off white liquid free from any visible particles. GEMCOVAC™-19 was found to be non-inferior to COVISHIELD™. Each dose of 0.5 mL contains 10 µg of GEMCOVAC™-19 mRNA Cellular Response: Cellular response was assessed in 122 subjects of vaccine. the immunogenicity cohort. Both COVISHIELD™ and GEMCOVAC™-19 4. CLINICAL PARTICULARS cohorts elicited vigorous spike-specific T-cell responses. These 4.1 Therapeutic indications responses were biased towards T helper 1 cell (Th1) cytokines (IFNγ and GEMCOVAC™-19 is indicated for active immunization of individuals TNFα) expression. Th2 cytokines (IL-4 and IL-13) expressions were very ≥18 years old for the prevention of COVID-19. minimal or undetectable in both the vaccinated cohorts. Additionally, COVISHIELD™ and GEMCOVAC™-19 cohorts showed spike-specific 4.2 Posology and method of administration poly-functional T-Cell responses. Both the vaccines showed elevated Posology spike-specific memory B-Cell populations as compared to their GEMCOVAC™-19 should be administered in two doses, second dose respective baseline. after 28 days of the first dose. A volume of 0.5 ml should be administered intramuscularly. It is recommended that individuals who receive a first 5.3 Pharmacokinetic properties dose complete the vaccination course with GEMCOVAC™-19. Evaluation of pharmacokinetic properties is not required for vaccines. Method of administration 6. NONCLINICAL PROPERTIES GEMCOVAC™-19 should be administered intramuscularly preferably in 6.1 Animal Toxicology or Pharmacology the deltoid muscle. A GLP- compliant repeat dose toxicity study was conducted in wistar rats. A dose of 25 µg / 0.5 ml was administered once in 2 weeks over a period of 4.3 Contraindications 4 weeks (days 1, 15 and 29) along with control. GEMCOVAC™-19 Hypersensitivity to any constituents of GEMCOVAC™-19 administered intramuscularly was well tolerated by the rats. Treatment Individuals below 18 years of age with GEMCOVAC™-19 did not cause any remarkable or adverse effects 4.4 Special warnings and precautions for use on the absolute and relative (% of body weight) values of weights of liver, • GEMCOVAC™-19 should not be administered intravenously, kidneys, adrenals, testes / uterus (with cervix), brain, lungs and heart of intradermally or subcutaneously. the rats in this study. The necropsy examination of all rats conducted at • Hypersensitivity and Anaphylaxis: There is a risk of hypersensitivity termination of the study did not reveal any incidence of treatment related reactions due to the constituents of GEMCOVAC™-19. Supervision systemic pathology. No mortality occurred during the duration of the study. GEMCOVAC™-19 was found to be safe, immunogenic and well and if needed the appropriate medical treatment should be provided tolerated at the sites of injections. to all the vaccine recipients after immunization. • Concurrent Illness: As with other vaccines, administration of Immunogenicity studies were conducted with GEMCOVAC™-19 in mice, GEMCOVAC™-19 should be postponed in individuals suffering from rats and hamsters. The vaccine elicited robust humoral (binding and an acute severe febrile illness. neutralizing antibodies), immune responses to the Spike antigen in • Risk of bleeding with intramuscular administration: As with other different animal models. intramuscular injections, GEMCOVAC™-19 should be given with Animal Challenge Study: GEMCOVAC™-19 efficacy in the prevention of caution to individuals with thrombocytopenia, any coagulation disorder SARS-CoV-2 infection was evaluated in virus challenge study conducted or to persons on anticoagulation therapy, because bleeding or bruising in Syrian Golden Hamsters. The results indicated that intramuscular may occur following an intramuscular administration in these administration of GEMCOVAC™-19 elicited immune responses that individuals. mitigated SARS-CoV-2 virus replication and pathogenesis significantly. • Immunocompromised Individuals: It is not known whether individuals The reduced viral replication and presence of SARS-CoV-2 neutralizing with impaired immune responsiveness, including individuals antibodies coincided with the reduced clinical signs and lung tissue receiving immunosuppressant therapy, will elicit the same response as pathology in vaccinated animals compared with the infected- immunocompetent individuals to the vaccine regimen. unvaccinated groups. • Anxiety related reactions: Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related 7. DESCRIPTION reactions may occur in association with vaccination as a psychogenic GEMCOVAC™-19 (COVID-19 mRNA Vaccine) is a lyophilized powder response to the needle injection. It is important that precautions are in that needs to be reconstituted with sterile water before injection. place to avoid injury from fainting. GEMCOVAC™-19 is supplied as a lyophilized powder in multiple dose • Interchangeability: There are no safety, immunogenicity or efficacy vials of 5 and 20 doses. For the 5 dose vial, draw 3 ml of water and for the data to support interchangeability of GEMCOVAC™-19 with other 20 dose vial, draw 11 ml of water and reconstitute the vial. Gently swirl the COVID-19 vaccines. vial intermittently for approximately 120 seconds till all the lyophilized • Reconstitution: contents are dissolved and no particles are visible. The solution should 5 Dose: GEMCOVAC™-19 is available as a lyophilized powder which be off white liquid free from any visible particles. Inject IM 0.5 mL of the needs to be reconstituted with Sterile Water for Injections I.P. Draw 3 ml reconstituted vaccine solution within 6 hours of reconstitution to the of water and reconstitute the vial. Gently swirl the vial intermittently for recipient. If not administered within 30 minutes after reconstitution, keep reconstituted vaccine back at +2ºC to +8ºC. Recipients who must be approximately 120 seconds till all the lyophilized contents are dosed on same day within 6 hours of reconstitution. dissolved and no particles are visible. The solution should be off white liquid free from any visible particles. Inject IM 0.5 mL of the 8. PHARMACEUTICAL PARTICULARS reconstituted vaccine solution within 6 hours of reconstitution to the One dose of vaccine (0.5 ml) contains: mRNA (10 μg), DOTAP (0.3 mg), recipient. If not administered within 30 minutes after reconstitution, Squalene (0.376 mg), Sorbitan Monostearate (0.372 mg), Polysorbate keep reconstituted vaccine back at +2ºC to +8ºC. This vaccine is 80 (0.372 mg), Citric Acid Monohydrate (1.05 mg) and Sucrose (50 mg). multi-dose. It will be used for dosing up to 5 recipients who must be 8.1 Incompatibilities dosed on same day within 6 hours of reconstitution. In the absence of incompatibility studies, the vaccine should not be mixed 20 Dose: GEMCOVAC™-19 is available as a lyophilized powder with any other medicinal products. which needs to be reconstituted with Sterile Water for Injections I.P. Draw 11 ml of water and reconstitute the vial. Gently swirl the vial 8.2 Shelf life intermittently for approximately 120 seconds till all the lyophilized The expiry date of lyophilized vaccine is indicated on the label and outer contents are dissolved and no particles are visible. The solution should pack. Once reconstituted, solution can be considered stable up to 6 hours be off white liquid free from any visible particles. Inject IM 0.5 mL of the when stored at +2ºC to +8ºC without opening flip off seal and rubber reconstituted vaccine solution within 6 hours of reconstitution to the stopper. All reconstituted multi-dose vials of GEMCOVAC™-19 should be recipient. If not administered within 30 minutes after reconstitution, discarded at the end of immunization session or within six hours keep reconstituted vaccine back at +2ºC to +8ºC. This vaccine is multi- whichever comes first. dose. It will be used for dosing up to 20 recipients who must be dosed 8.3 Packaging information on same day within 6 hours of reconstitution. GEMCOVAC™-19 Lyophilized mRNA Vaccine for Injection (COVID-19) 4.5 Drug interactions is supplied in USP type I glass vial with Bromo-butyl rubber stopper and The safety, immunogenicity and efficacy of co-administration of Flip-off Aluminium seal. GEMCOVAC™-19 with other vaccines or medications have not been 8.4 Storage and handling instructions evaluated. Store in a refrigerator (+2ºC to +8ºC). Do not freeze or shake the 4.6 Use in special populations reconstituted solution. The vials should be used within 6 hours once Safety, efficacy and immunogenicity have not been established in opened. The vaccine should not be used beyond the expiry date as mentioned in the label. pregnant women and nursing mothers. It is unknown if GEMCOVAC™-19 is excreted in human milk. 9. PATIENT COUNSELLING INFORMATION Paediatric population: The safety and efficacy of GEMCOVAC™-19 has GEMCOVAC™-19 is a mRNA-based vaccine which uses Spike (S)- not been established in children and adolescents < 18 years of age. protein of the SARS-CoV-2 virus as an antigen. The body is expected to Elderly population: No dose adjustment is required for the elderly. develop an immune response post vaccination which will help in prevention of severe COVID-19 disease. The most common adverse 4.7 Effects on ability to drive and use machines events reported with GEMCOVAC™-19 include injection site pain, fever No studies on the effect of GEMCOVAC™-19 on the ability to drive or use and headache. machines have been performed. Inform the vaccine recipient of the potential benefits and risks of 4.8 Undesirable effects vaccination with GEMCOVAC™-19 and the importance of completing the Safety data from Phase I Clinical Trial 2 dose vaccination series. Advice the recipients to report any adverse The Phase I clinical trial was conducted in 82 healthy subjects between event to their healthcare provider and by writing to Safety@gennova.co.in the age of 18 and 70 years. Three dose strengths of 5 μg, 10 μg and 25 μg 10. DETAILS OF MANUFACTURER were compared with placebo. The primary endpoint of this study was to GEMCOVAC™-19 is manufactured and Marketed by: assess the safety, reactogenicity and tolerability of GEMCOVAC™-19 at Gennova Biopharmaceuticals Limited the three dose strengths following 2 doses administered 28 days apart. Block 1, Plot No. P-1 & P-2, I.T.B.T. Park, Local Solicited Adverse Event: There was no significant difference Phase II, MIDC, Hinjawadi, Pune - 411 057, India. among the three dose strengths. The most frequent local adverse event TM Trade Mark Owned by was injection site pain, followed by induration/swelling and Gennova Biopharmaceuticals Ltd. erythema/redness. Most of the solicited local AEs were of Grade 1 intensity. No immediate solicited AEs or solicited AEs of Grade 3 and 11. DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE above intensity were reported. MF/BIO/22/000064 dated 28-JUN-2022 under PD/Vacc-6 Systemic Solicited Adverse Event: The occurrence of systemic solicited 12. DATE OF REVISION adverse events was comparable between all dose strengths. Fatigue 02nd July 2022 was most commonly reported, followed by headache and fever. Myalgia and chills were reported in less than 30% of the participants. Most of the solicited systemic AEs were of Grade 1 intensity. None of the adverse events were of Grade 3 and above as per the DAIDs criteria. Unsolicited Adverse Events: All unsolicited adverse events except 5 were considered not related. The related adverse events were laboratory (1) Front 20NI335020015 Time Age 18 - ≤ 40 years > 40 - ≤ 60 years > 60 years Point (n = 349) (n = 114) (n = 14) Day 43 [% (SD)] 94.5 (6.38) 95.5 (3.44) 96.7 (0.51) 551 Time Point GEMCOVAC™-19 COVISHIELD™ (n = 27) (n = 13) Baseline at Day 1 14.7 (7.7 – 27.9) 10.9 (4.2 – 27.8) [GMT (95% CI)] Day 43 323.6 (160.3 – 653.0) 384.4 (142.8 – 1034.7) [GMT (95% CI)] (4)mm 024 180 mm abnormalities which resolved completely. Most of the unsolicited AEs Musculoskeletal and Common Myalgia, Arthralgia were of Grade 1 severity. No Grade 3 or higher adverse event was connective tissue disorders observed in participants receiving GEMCOVAC™-19. None of the Nervous System Disorders Very Common Headache adverse events led to death. Gastrointestinal Disorders Common Nausea Serious Adverse Events: No related serious adverse events were Uncommon Vomiting observed in this study. Respiratory, thoracic and Uncommon Influenza like illness Safety data from Phase II Clinical Trial mediastinal disorders The Phase II clinical trial was conducted in 415 participants. The safety and immunogenicity of GEMCOVAC™-19 was compared with the No cases of myocarditis/pericarditis (Adverse Event of Special Interest) approved vaccine COVISHIELD™. The participants were randomized to were reported in Phase I, II and III clinical trial. the two arms in a 1:1 ratio. 4.9 Overdose Table 1. Phase II clinical trial demography There is no data on overdose of GEMCOVAC™-19. Demography GEMCOVAC™-19 COVISHIELD™ 5. PHARMACOLOGICAL PROPERTIES (n = 207) (n = 208) 5.1 Mechanism of action Age [Median (min., max.)] 33.0 (18, 74) 34.0 (18, 69) GEMCOVAC™-19 uses the Spike (S) - protein of the SARS-CoV-2 virus as antigen which is reported to interact with host cells receptors (ACE-2). Male/Female [n] 137/70 138/70 It uses a self-amplifying mRNA platform for slow and sustained release of Weight [Mean (SD)] 62.6 (12.82) 60.9 (10.22) S-protein for longer duration along with CLNE system for targeted BMI [Mean (SD)] 23.75 (4.37) 23.29 (3.99) vaccine delivery. Once administered intramuscularly, the in vitro transcribed mRNA encoding the S-protein is translated in the cytosol of Co-morbid Conditions the cells utilizing the cellular translational machinery. The S-protein Anaemia [n (%)] 3 (1.4) 4 (1.9) synthesized represents the antigen, which then elicits the potent humoral Hypothyroidism [n (%)] 0 1 (0.5) and cellular immune responses. Diabetes Mellitus [n (%)] 3 (1.4) 3 (1.4) 5.2 Pharmacodynamic properties Asthma [n (%)] 0 1 (0.5) Immunogenicity from Phase I Clinical Trial A dose-ranging (5 μg, 10 μg and 25 μg), placebo-controlled, Phase I Hypertension [n (%)] 0 1 (0.5) study was conducted in 82 health individuals between 18-70 years of Local Solicited Adverse Events: A total of 107 participants (51.7%) age. receiving GEMCOVAC™-19 experienced at least one solicited local Anti-Spike IgG antibodies: There was a statistically significant rise in the adverse event compared to 79 participants (38.0%) in the anti-S- IgG GMT at Day 57 compared to baseline (Day 1) in the 5 μg, 10 COVISHIELD™ arm. Although the local solicited events were higher in μg and 25 μg. The GMT at Day 57 were 6408 (95% CI: 2330 – 17624) for the GEMCOVAC™-19 arm, this difference was restricted to Grade 1 and the 5 μg group, 17013 (95% CI: 7115 – 40682) for the 10 μg group, 16266 2 intensities. The Grade 3 and above adverse events were comparable (95% CI: 5777 – 45801) for the 25 μg group and 781 (95% CI: 397– 1535) between the two vaccine arms. In participants receiving in the placebo group. GEMCOVAC™-19, pain at injection site was the most commonly cPASS Neutralization Assay: The cPass SARS-CoV-2 Surrogate observed event (47.3% of participants), followed by warmth (16.4% of Neutralization Antibody assay (Genscript) measures the neutralizing participants), swelling/induration (9.2% of participants), erythema (2.4% antibodies in blood sera of the participants. Sera collected from of participants), pruritus (1.9% of participants) and bruising (0.5% of participants at Day 57 showed a high neutralization capacity of 97%, 96% participants). and 93% for the 5 μg, 10 μg and 25 μg groups respectively. Systemic Solicited Adverse Events: A total of 100 participants (48.3%) Immunogenicity from Phase II Clinical Trial receiving GEMCOVAC™-19 experienced at least one solicited systemic In Phase II, the immunogenicity of GEMCOVAC™-19 was compared with adverse event compared to 93 participants (44.7%) in the COVISHIELD™ arm at any dose. In the participants who received that of COVISHIELD™ at Day 43. Anti-Spike IgG Antibody: At Day 43, the IgG GMT was 216320 (95% GEMCOVAC™-19, headache was most commonly observed (28.0% of participants), followed by fatigue (27.1% of participants), fever (23.7% of CI:178561 - 262063) in the COVISHIELD™ arm and 282464 (95% participants), myalgia (22.2% of participants), chills (17.4 % of CI:233994 - 340974) in the GEMCOVAC™-19 arm. The Least Square participants), malaise (12.6% of participants), arthralgia (12.1% of Geometric Mean Ratio (GEMCOVAC™-19: COVISHIELD™) was 1.267 participants) and nausea (6.3% of participants). Most of the solicited and there was no statistically significant difference between the two. systemic adverse events were of Grade 1 intensity. Four subjects (1.9%) PRNT50 Assay: Plaque reduction neutralization test (PRNT) analysis in the GEMCOVAC™-19 arm and 3 (1.4%) in the COVISHIELD™ arm was performed in a subset of the population in the two groups. At Day 43, reported solicited adverse events of Grade 3. One subject (0.5%) in the the PRNT50 GMT were 1085 (95% CI: 718 – 1639) in the COVISHIELD™ GEMCOVAC™-19 arm and 2 (1.0%) in the COVISHIELD™ arm reported arm and 802 (95% CI: 420 – 1532) in the GEMCOVAC™-19 arm. There solicited adverse event of Fever of Grade 4 intensity. was no statistically significant difference in the PRNT50 GMT at day 43 Unsolicited Adverse Events: A total of 20 participants (9.7%) in the between the two groups. GEMCOVAC™-19 arm and 25 participants (12.0%) in the cPASS Neutralization Assay: At Day 43, the neutralization capacity was COVISHIELD™ arm observed at least 1 unsolicited event following any at 93.3% (standard deviation: 9.99) in the COVISHIELD™ arm and vaccination. Of these adverse events, 5 in the GEMCOVAC™-19 arm 86.9% (standard deviation: 24.61) in the GEMCOVAC™-19 arm. There were termed vaccine related (2 incidences of chest pain, 1 incidence of was no statistically significant difference between the two groups at Day injection site pain, 1 incidence of dizziness and 1 incidence of urticaria). 43. Serious Adverse Events: A total of 8 serious adverse events were Seroconversion: Seroconversion rate assessed by a ≥ 2-fold rise in anti- reported out of which 1 was fatal and related to COVISHIELD™ Spike IgG titer in seropositive subjects and ≥ 4-fold rise in anti-spike IgG (Pulmonary Embolism). Other adverse events were termed not related to titer in seronegative subjects at Day 43 was similar in both the groups vaccine. (91.2% in GEMCOVAC™-19 and 93.7% in COVISHIELD™). Safety data from Phase III Clinical Trial Cellular Immune Responses: T-cell responses against the spike protein The Phase III clinical trial was conducted in 4000 participants who were were assessed by using flow-cytometry based intracellular randomized to receive either GEMCOVAC™-19 or COVISHIELD™ in a cytokine–staining (ICS) assay, on peripheral blood mononuclear cells 3:1 ratio. (PBMCs). Both COVISHIELD™ and GEMCOVAC™-19 cohorts showed Table 2. Phase III clinical trial demography spike peptides stimulated IFNγ expression in CD4+ T-Cell at day-29. COVISHIELD™ cohort showed relatively higher IFNγ expressions in Demography GEMCOVAC™-19 COVISHIELD™ CD4+ T-cells, whereas GEMCOVAC™-19 generated relatively higher (n = 2992) (n = 998) spike stimulated IL-2 expressions in CD4+ T-Cells. Both COVISHIELD™ Age [Median (min., max.)] 33.0 (18, 81) 33.0 (18, 79) as well as GEMCOVAC™-19 showed similar TNFα expressions in both Male/Female [n] 2348/644 781/217 CD4+ and CD8+ T-cells. Th2 cytokines (IL-4 and IL-13) expressions were very minimal or undetectable in both the vaccinated cohorts. Weight [Mean (SD)] 61.2 (11.30) 61.3 (11.20) Immunogenicity from Phase III Clinical Trial BMI [Mean (SD)] 22.46 (3.78) 22.53 (3.90) In Phase III non-inferiority study, the immunogenicity of GEMCOVAC™-19 Co-morbid Conditions was compared to COVISHIELD™ at Day 43 in 714 subjects. Hypertension 13 (0.4) 2 (0.2) GEMCOVAC™-19 was compared to COVISHIELD™ at Day 43 in 714 subjects. History of hysterectomy [n (%)] 9 (0.3) 1 (0.1) Anti-Spike IgG Antibodies: Anti-Spike IgG antibodies were compared in a Hypothyroidism [n (%)] 4 (0.1) 0 total of 714 participants of which 237 received COVISHIELD™ and 477 Diabetes Mellitus [n (%)] 10 (0.3) 0 received GEMCOVAC™-19. There was a statistically significant rise in antibodies in both groups from baseline to Day 43. The GMT of Uterine leiomyoma [n (%)] 1 (0) 0 GEMCOVAC™-19 was found to be non-inferior to COVISHIELD™. Asthma [n (%)] 1 (0) 0 Table 4. Anti-spike IgG antibodies in Phase III study Local Solicited Adverse Events: A total of 928 (31.0%) of the participants receiving GEMCOVAC™-19 and 263 (26.4%) of the participants Time Point GEMCOVAC™-19 COVISHIELD™ receiving COVISHIELD™ experienced at least one local solicited (n = 477) (n = 237) adverse event. In the participants receiving GEMCOVAC™-19, pain at Baseline at Day 1 11647.8 10200.0 the injection site was the most common local solicited reaction (27.5% of [GMT(95% CI)] (9956.4 - 13626.6) (8018.9 - 12974.4) participants), followed by swelling at injection site (3.6% of participants), Day 43 339930.2 319605.1 warmth at injection site (3.1% of the participants), redness at injection site [GMT(95% CI)] (311391.4 - 371084.5) (281630.1 - 362700.6) (1.7% of participants), pruritus (0.4% of the participants) and bruising (0.1% of participants). None of the adverse events were above Grade 2. The anti-Spike IgG antibodies were also analyzed in 3 groups stratified by Systemic Solicited Adverse Events: A total of 955 (31.9%) participants age (18 - ≤ 40, > 40 - ≤ 60 and > 60 years). There was no reduction in the receiving GEMCOVAC™-19 and 340 (34.1%) participants receiving Anti-Spike IgG titer at Day 43 with GEMCOVAC™-19 and no dose COVISHIELD™ observed at least 1 systemic solicited adverse event. In adjustment is required for older age groups more than 60 years of age. participants receiving GEMCOVAC™-19, the most common systemic solicited event was fever (15.6% of participants) followed by headache Table 5. Anti-Spike IgG Antibodies at Day 43 in participants (12.9% of participants), fatigue (7.2% of participants), myalgia (6.9% of receiving GEMCOVAC™-19 stratified by age ap ra tr ht ric ai lp ga ian ts (1), . 3c %hil ls o ( f 4 p.9 a% rti co if p p aa nr tt sic ) ip aa nn dt s) n, a m ua sela ais e (1 ( .1 3. %7% o o f f pp aa rr tt ii cc ii pp aa nn tt ss )) ., PT oim ine t Age 18 (- n ≤ =4 0 3 4y 9e )ars > 40 ( n- ≤ = 6 10 1 4y )ears > (6 n0 = y 1e 4a )rs Vomiting and influenza like illness was seen in < 1% of participants. Day 43 322099.8 369352.3 662433.1 Unsolicited Adverse Events: A total of 51 (1.7%) participants receiving GEMCOVAC™-19 and 15 (1.5%) of participants receiving [GMT(95% CI)] (290152.0 - (311528.3 - (441229.4 - COVISHIELD™ observed at least one solicited adverse event. In the 357565.2) 437909.4) 994533.8) GEMCOVAC™-19 arm, of the 4 events were considered related to the vaccine (chest pain, uterine haemorrhage, angioedema and pruritus). PRNT50 Assay: PRNT50 analysis was performed using the D614G Serious Adverse Events: A total of 10 serious adverse events (7 in variant of SARS-CoV-2 in 76 participants. There was a substantial GEMCOVAC™-19 and 3 in COVISHIELD™) were observed. One increase in the neutralizing antibodies in both the arms from baseline till serious adverse event of fever in COVISHIELD™ arm was related to the Day 43. Neutralizing antibody GMT in GEMCOVAC™-19 arm was found vaccine. The causality assessment of 1 serious adverse event in to be comparable to COVISHIELD™ arm. GEMCOVAC™-19 arm (Abnormal Uterine Bleeding) was considered as Table 6. Neutralization by PRNT50 assay against D614G variant of 'possibly related'. SARS-CoV-2 in Phase III study Adverse drug reactions observed during the clinical trials were Time Point GEMCOVAC™-19 COVISHIELD™ ranked using the following conventions: (n = 51) (n = 25) Very Common :≥ 1/10 Baseline at Day 1 29.3 (16.7 - 51.6) 31.1 (13.6 - 70.9) Common :≥ 1/100 to < 1/10 [GMT(95%CI)] Uncommon :≥ 1/1000 to < 1/100 Day 43 1099.9 (817.9 – 1479.2) 841.6 (461.5 – 1534.8) Rare :≥ 1/10000 to < 1/1000 [GMT(95%CI)] Table 3. Adverse Events Observed in Phase III Clinical trial with cPASS Neutralization Assay: cPASS assay was performed in all 714 GEMCOVAC™-19 participants of the immunogenicity cohort. There was a statistically MedDRA System Frequency Adverse Event significant rise in the neutralizing antibodies in both the groups from Organ Class baseline to Day 43. The percent neutralization was comparable in both General Disorders and Very Common Pain/Tenderness, groups at Day 43. Administration Site Fever Table 7. Neutralization by cPASS assay in Phase III study Conditions Common Redness/Erythema, Time Point GEMCOVAC™-19 COVISHIELD™ Swelling/Induration, (n = 477) (n = 237) Warmth, Chills, Malaise, Fatigue Baseline at Day 1 [% (SD)] 44.8 (33.75) 44.5 (34.40) Uncommon Pruritus, Bruising Day 43 [% (SD)] 94.8 (5.74) 93.9 (7.59) (2) (3) Back