Novavax/ Serum Institute of India (SII) COVID-19 vaccine

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Extended version of the vaccine

Novavax/ Serum Institute of India (SII) COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

Novavax COVID-19 vaccine
Listed for emergency use on 20 December 2021 [WHO, 2022 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 12 years of age and older [WHO, 2022 ].
SAGE/WHO Recommendation: Recommended for individuals 12 years of age and older [WHO, 2022 ].
Serum Institute of India COVID-19 vaccine
Listed for emergency use on 17 December 2021 [WHO, 2021 ].

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use (Conditional Marketing Authorization).
20 December 2021: For individuals 18 years of age and older [EMA, 2022 ].
23 June 2022: For individuals from 12 to 17 years of age [EMA, 2022 ].

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized.

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized.

Health Canada
Authorized on 17 February 2022 [Health Canada, 2022 ].

Public Health Institute (ISP, Chile)
Not authorized.

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Not authorized.

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized.

U.S. Food and Drug Administration (FDA)
Authorized for emergency use [FDA, 2022 ].
13 July 2022: Emergency Use Authorization (EUA) for individuals 18 years of age and older.
August 19, 2022: Emergency Use Authorization (EUA) for individuals aged 12 to 17 years [FDA, 2022 ]

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Not authorized.

Authorization in jurisdictions in Latin America and the Caribbean
Not authorized.

Authorization in other jurisdictions
Australia
Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
India
Indonesia
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
New Zealand
Norway
Oman
Philippines
Poland
Portugal
Romania
Singapore
Slovakia
Slovenia
South Korea
Spain
Sweden
Switzerland
United Kingdom
United States of America

The Emergency Use Authorization does not constitute marketing authorization in the country.

Manufacturing

Manufacturers
Novavax CZ, Czech Republic [WHO, 2022 ]
NVX- CoV2373 is marketed as NuvaxovidTM and COVOVAXTM. These vaccines are considered fully equivalent, even if produced at different manufacturing sites or assigned different product names.

Drug substance [WHO, 2022 ].
Serum Institute of India Pvt. Ltd., Hadapsar, Pune - 411028, India.
Serum Institute of India Pvt. Ltd., Manjari BK, Tal -Haveli, Pune, India.

Drug Product [WHO, 2022 ].
Serum Institute of India Pvt. Ltd., Manjari BK, Tal-Haveli, Pune, Maharashtra, India.


Other manufacturers

Manufacturers of the antigen component of the vaccine [NOVAVAX, 2020 ]
Novavax CZ (formerly Praha Vaccines), Bohumil, Czech Republic.
Biofabri, Spain.
FUJIFILM Diosynth Biotechnologies (FDB), North Carolina and Texas, United States, Teesside, United Kingdom.
SK Bioscience, Republic of Korea.
Takeda Pharmaceutical Company Limited, Japan.

General characteristics

The Novavax COVID-19 vaccine is described as a recombinant nanoparticle vaccine (SARS-CoV-2 rS). It can be described as both a protein subunit vaccine and a virus-like particle vaccine. The recombinant nanoparticle is a SARS-CoV-2 spike protein stabilized in its pre-fusion form [Keech C, 2020 ].

The recombinant SARS-CoV-2 spike (S) protein nanoparticle (SARS-CoV-2 rS) is constructed from the full-length wild-type SARS-CoV-2 S glycoprotein based on the GenBank MN908947 gene sequence, nucleotides 21563 to 25384. The protein S is a trimeric type 1 glycoprotein, composed of 1273 amino acids that are produced as an inactive precursor of S0. The S gene has a codon optimized for its expression in Spodoptera frugiperda (Sf9) insect cells [Keech C, 2020 ].

The nanoparticle is produced in the established Spodoptera frugiperda (Sf9) insect cells expression system which consists in Sf9 moth cells that are infected by an engineered baculovirus creating the nanoparticle and displaying it on their cell membranes [Smith GE, 1986 ]. The nanoparticles are then harvested and assembled onto a synthetic lipid nanoparticle [Keech C, 2020 ].

The adjuvant is Matrix-M, a saponin-based adjuvant. Matrix-M1 adjuvant has been shown to result in dose sparing and induced strong/high levels of CD4+ effector memory T-cell responses that were also biased toward a Th1 phenotype that may play a role in reducing the theoretical possibility of antibody-dependent enhancement of SARS-CoV-2 infection [Karthik K, 2020 ].

Ingredients


The vaccine contains the following ingredients:

Active ingredient
SARS-CoV-2 rS (5 µg)

Adjuvant
Matrix-M1 (50 µg)

Excipients
Disodium hydrogen phosphate heptahydrate
Sodium dihydrogen phosphate monohydrate
Disodium hydrogen phosphate dihydrate
sodium chloride
Polysorbate 80
Cholesterol
Phosphatidylcholine (including all-rac-α-Tocopherol)
Potassium dihydrogen phosphate
Potassium chloride
Sodium hydroxide (for the adjustment of pH)
Hydrochloric acid (for the adjustment of pH)
Water for Injections

Risk considerations

Peptide-based vaccines have theoretical advantages over traditional whole-organism and other platforms. They allow the immune response to focus on the protective epitopes and to exclude non-relevant epitopes, including those reactogenic or allergenic, at the stage of vaccine design [Reche PA, 2014 ].

Dosing and schedule

The Novavax COVID-19 vaccine is administered as a series of two doses (5 μg of recombinant spike protein with 50 μg of Matrix-M adjuvant per 0.5 mL dose) with an interval of 3–4 weeks between doses. Based on the evidence of reduced risk of myocarditis or pericarditis after vaccination with an extended interval between first and subsequent doses in persons receiving mRNA COVID-19 vaccines, an 8-week interval is recommended between primary series doses of NVX-CoV2373 as a precaution [WHO, 2022 ].

The pharmaceutical form is a dispersion for intramuscular injection provided in a multidose vial (10 doses of 0.5 mL per vial) [WHO, 2022 ].
The preferred site of injection is the deltoid muscle of the upper arm.

If administration of the second dose is inadvertently delayed beyond 4 weeks, it should be given as soon as possible.


Booster dose [EMA, 2022 ]
The first booster dose is recommended for the highest priority use groups, 4 to 6 months after completion of the primary series. To further reduce the risk of serious illness, a second booster dose may be considered 4 to 6 months after the first booster dose for all older people. For adolescents 12 to 18 years of age, there is currently insufficient evidence to recommend a booster dose, except for those with immunocompromised conditions. [WHO, 2022 ]

A heterologous booster dose using the Novavax COVID-19 vaccine may be given after an mRNA-based or adenoviral vector vaccine.

Second booster dose:
WHO recommends considering a second booster dose 4-6 months after the first booster dose for all older persons (age-specific cutoff defined by countries), all persons with moderate and severe immunocompromising conditions -regardless of age-, adults with comorbidities that put them at higher risk of severe disease, pregnant women, and health workers [WHO, 2022 ].


Heterologous schedule [WHO, 2022 ]
WHO supports a flexible approach to using different EUL COVID-19 vaccine products for different doses (heterologous schedule), and considers a total of 2 doses of any combination of EUL COVID-19 vaccines to be a complete primary series.

Heterologous vaccination should only be implemented with careful consideration of current vaccine supply, vaccine supply projections, and other access considerations, alongside the potential benefits and risks of the specific products being used.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends and extended primary series including an additional (third) dose for immunocompromised persons aged 18 years and older, administered 1–3 months after the second dose in the standard primary series.

A booster (fourth) dose administered 4–6 months after the additional (third) dose should be considered for immunocompromised persons.

Indications and contraindications

Indications

The Novavax COVID-19 vaccine is indicated for individuals 12 years of age and over [WHO, 2022 ].

For prioritization by age and other considerations, refer to the WHO Prioritization Roadmap [WHO, 2022 ]

WHO recommends the use of Novavax COVID-19 vaccine in pregnant persons.

Contraindications

Novavax COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the Novavax COVID-19 vaccine [WHO, 2022 ].

The second dose of the vaccine should NOT BE GIVEN to those who have experienced immediate allergic reaction to the first dose of Novavax COVID-19 vaccine [WHO, 2022 ].

Close observation for at least 30 minutes is recommended following vaccination.

Precautions

Allergic reactions [WHO, 2022 ].
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed for 30 minutes after vaccination in health care settings where anaphylaxis can be immediately treated.

The Novavax COVID-19 vaccine should be administered under medical supervision, with an observation period of 15 minutes after vaccination and appropriate medical treatment available in case of allergic reactions.

Myocarditis and pericarditis [WHO, 2022 ].

Myocarditis and pericarditis are very rare adverse events that have been reported after receiving the Novavax COVID-19 vaccine. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms indicative of myocarditis or pericarditis, such as new onset and persisting chest pain, shortness of breath, or palpitations following vaccination.

Pregnancy [WHO, 2022 ].
WHO recommends the use of Novavax COVID-19 vaccine in pregnant persons.

WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination.

Breastfeeding [WHO, 2022 ].
WHO recommends using the Novavax COVID-19 vaccine in breastfeeding as in non-breastfeeding women. This is based on the following considerations: (a) Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults, and (b) Novavax COVID-19 is not a live virus vaccine, and it is biologically and clinically unlikely to pose a risk to the breastfeeding child.
WHO does not recommend discontinuing breastfeeding after vaccination.

Children and adolescents [WHO, 2022 ].
Adolescents aged 12 to 17 years with comorbidities that put them at higher risk of serious COVID-19-related disease should be offered vaccination.

Older persons [WHO, 2022 ].
Vaccination is recommended for older persons without an upper age limit.

Persons living with HIV [WHO, 2022 ].
Preliminary findings highlight the safety and immunogenicity of the Novavax vaccine on PLWH. Nevertheless, their immune response to the vaccine may be reduced.
Given that the vaccine is nonreplicating, persons living with HIV who are well controlled may be vaccinated with the standard primary series of two doses. Counseling should be provided to inform the individual benefit-risk assessment.


Persons with previous SARS-CoV-2 infection [WHO, 2022 ].
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
The optimal time interval between a natural infection and vaccination is not yet known. An interval of 3 months could be considered.

Persons with current acute COVID-19 [WHO, 2022 ].
Persons with acute PCR-confirmed COVID-19 should not be vaccinated until after they have recovered from acute illness and the criteria for discontinuation of isolation have been met.

Persons who previously received passive antibody therapy for COVID-19[WHO, 2022 ]
Although some reduction in vaccine-induced antibody titers has been observed in this group, the balance of benefits versus risks favors vaccination.

Other precautions [WHO, 2022 ].
Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5ºC) until they are afebrile.

A few cases of paraesthesia and hypoesthesia have also been reported after receiving the Novavax COVID-19 vaccine. Continued monitoring and surveillance of these conditions with the use of the Novavax COVID-19 vaccine is recommended.

Co-administration with other vaccines [WHO, 2022 ].
Inactivated influenza vaccine
The Novavax COVID-19 vaccine can be co-administered with inactivated influenza vaccines. Co-administration studies demonstrated the safety and immunogenicity of the seasonal influenza vaccine and the NVX-CoV2373 vaccine.
Different arms for injection should be used when both vaccines are delivered during the same visit.

Storage and logistics

Storage

The Novavax COVID-19 vaccine must be stored refrigerated between 2°C to 8°C [35° to 46°F] [WHO, 2022 ].
Protect the vials from light.
Do not freeze.

Administration logistics

Inspect the vial before use.
The vial should be discarded if particles or differences are observed in the described appearance of the vaccine.
Before administering a dose of vaccine, invert the vaccine in an upright position for 10 seconds. Do not shake.

Storage after first puncture

After the first puncture of the monodose vial, use immediately.
Once the multidose vial of the vaccine is opened, it can be stored between 2°C and 8°C (36 ° F to 46 ° F) for up to 6 hours or until the last dose is used, whichever occurs first.
Record the date and time the vial should be discarded.
To improve traceability, the name and batch number of the administered product should be clearly recorded.

Administration

1. Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 ml reuse prevention syringe (RUP) or a 5 ml RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix and withdraw the 0.5 ml dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 ml dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Disposal

Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

The following randomized clinical trials have reported vaccine efficacy and/or safety data:

Phase 1/2:
The TAK-019 trial (registry number NCT04712110 [Takeda, 2021 ]) conducted in Japan included 200 participants aged 20 and older since February 2021. 150 participants received two doses of the Novavax COVID-19 vaccine (5 μg SARS-CoV-2 rS; 50 μg Matrix-M1) and 50 participants placebo, 21 days apart. [Masuda T, 2022 ].

The 2019nCoV-101 trial (NCT04368988, [Novavax, 2020 ]) conducted in Australia and the United States since August 2020, included 1,610 participants aged 18 to 59 years old, distributed in the placebo group, the Novavax-placebo group, and the Novavax-Novavax group [Mallory RM, 2022 ], [Formica N, 2021 ], [Keech C, 2020 ], [Keech C, 2020 ], [Katherine Smith, 2023 ]

Phase 2:
The 2019nCoV-501 trial (NCT04533399 [Novavax, 2020 ]) conducted in South Africa included 4164 HIV-negative participants (2089 in the intervention group and 2075 in the placebo group) and 244 persons living with HIV-1 (122 in the intervention group and 122 in the placebo group) 18 years and older since August 2020. Participants received two doses of the Novavax vaccine or placebo 21 days apart [Masuda T, 2022 ], [Shinde V, 2021 ].

The COV-BOOST trial (ISRCTN73765130, [University Hospital Southampton NHS Foundation Trust, 2021 ]), conducted in the UK since June 2021 included 2,878 participants who were randomized 1:1:1:1 into Group A, 1:1:1:1:1 in group B and 1:1:1:1 in group C to receive an experimental or control vaccine as booster dose after a primary schedule of the AstraZeneca or Pfizer-BioNTech COVID-19 vaccine. The intervention was administered as follows: group A received Novavax, half-dose Novavax, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY); group B received Pfizer, Valneva, half-dose Valneva, Janssen, or MenACWY; group C received Moderna, CureVac, half-dose Pfizer, or MenACWY. [Munro, Alasdair P S, 2021 ], [Munro APS, 2022 ], [Liu X, 2022 ].

Phase 2/3:
The ICMR/SII-COVOVAX trial [Serum Institute of India Private Limited Pune, 2021 ] conducted in India included 1,600 adults, and 920 children and adolescents. In phase two, 200 participants were randomized 3:1 to Covovax vaccine or placebo, respectively. In phase three, 1,400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (Nuvaxovid™), respectively; among them, 940 were in the safety cohort, and 460 in the immunogenicity and reactogenicity cohort [Bhagwat Gunale, 2023 ] [Prasad S. Kulkarni, 2022 ], [Kulkarni PS, 2023 ].

Phase 3:
The 2019nCoV-302 trial (NCT04583995 [Novavax, Inc., 2020 ]) conducted in the United Kingdom since September 2020 included 15,187 participants aged 18 to 84 years. 7569 received two doses of the Novavax COVID-19 vaccine and 7570 received placebo, 21 days apart [Seth Toback, 2021 ], [Heath PT, 2022 ], [Heath PT, 2021 ].

The PREVENT-19 trial (NCT04611802 [Novavax, 2020 ]) conducted in the United States and Mexico during the first quarter of 2021 included 29,949 participants who were randomized in a 2:1 ratio. The first group received two doses of the Novavax vaccine and the second group received placebo 21 days apart [Lisa M. Dunkle, 2021 ], [Granwehr BP, 2022 ], [Dunkle LM, 2021 ], [Fong Y, 2023 ].
The expansion for adolescents 12 to 18 years of age was conducted in the United States and included 2,247 participants between April and June 2021, allocated to the Novavax COVID-19 vaccine or placebo 2:1, 21 days apart [Germán Áñez, 2022 ].

The COVOVAX-Booster trial (CTRI/2022/04/042017 [Kulkarni P, 2023 ]), conducted in India. Started in April 2022, included 372 previously vaccinated adults with ChAdOx1 nCoV-19 (n = 186) or BBV152 (n 6 1=1) less than six months, they were randomized to receive either a booster of SII-NVX-CoV2373 or a control vaccine. [Serum Institute of India Private Limited Pune, 2022 ]

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

Immunogenicity of the vaccine was evaluated in baboons and mice. Mice were immunized with 0.01 μg, 0.1 μg, 1 μg and 10 μg) of the vaccine with 5 μg Matrix-M adjuvant using a single priming dose or a prime/boost regimen spaced 14 days apart. In mice, low-dose plus adjuvant elicited high titer anti-S IgG that blocked hACE2 receptor binding, neutralized virus, and protected against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. The vaccine also elicited multifunctional CD4+ and CD8+ T cells, CD4+ follicular helper T cells, and antigen-specific germinal center B cells in the spleen. In baboons, low-dose vaccine plus adjuvant was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that blocked S-protein binding to hACE2 and neutralized virus infection [Tian JH, 2021 ].

Immunogenicity was tested in non-human primates (rhesus macaques), immunized with 2 different antigen doses (5 and 25μg) with Matrix-M adjuvant (50μg), with one vaccine dose (study day 0) or two vaccine doses, spaced 3 weeks apart (study day 0 and 21). Both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles. Anti-S IgG titers remained stable at 31/32 days after the first dose and anti-S IgG titers significantly increased 21–35-fold within 10 days following the booster immunization with 5μg or 25μg of the vaccine [Matthew J Gorman, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

TAK-019-1501 was a phase 1/2 trial that evaluated the safety and immunogenicity of two doses of NVX-CoV2373 vaccine. Following two doses of NVX-CoV2373 vaccine, given 21 days apart, serum IgG antibody levels to SARS-CoV-2 spike protein were recorded for all participants in the NVX-CoV2373 arm from baseline by day 36. IgG antibodies levels was not observed in the placebo group [Masuda T, 2022 ].

PREVENT-19 was a phase 3 trial that evaluated the efficacy and immunogenicity of two doses of the Novavax COVID-19 vaccine in adolescents (12 to 18 years old). Post-vaccination, the ratio of neutralizing antibodies geometric mean titers in adolescents compared to young adults was 1.5 (95% confidence interval [CI] 1.3 to 1.7) [Germán Áñez, 2022 ].

ICMR/SII-COVOVAX was a phase 3 trial that evaluated the safety and immunogenicity comparing SII-NVXCoV2373 to NVX-CoV2373. Results showed that 14 days after the second dose, the geometric mean concentrations as EU (GMEU) ratio between vaccine groups was 0.91 (95% CI, 0.79-1.06). Seroconversion was reached in 92.9% and 96.3% of the participants 14 days after the second dose in the SII-NVX-CoV2373 and the NVX-CoV2373 group, respectively. [Prasad S. Kulkarni, 2022 ][Germán Áñez, 2022 ][Kulkarni PS, 2023 ].

Key messages

Novavax COVID-19 vaccine reduces the risk of contracting COVID-19

Novavax COVID-19 vaccine reduces the risk of contracting severe COVID-19

Main efficacy outcomes of Novavax/Serum Institute of India (SII) COVID-19 vaccine

Contracting COVID-19 (measured at least 7 days after the second injection with a median follow-up of 3 months)

The relative risk of contracting COVID-19 in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 0.1 (95% CI 0.07 to 0.16). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine reduced the risk of contracting COVID-19 by 90%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Novavax/Serum Institute of India (SII) COVID-19 vaccine versus control vaccine

In the available trial, 159 people not receiving Novavax/Serum Institute of India (SII) COVID-19 vaccine out of 15159 presented this outcome (10 per 1000) versus 24 out of 24332 in the group that did receive it (1 per 1000). In other words, 9 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.9%, or that the intervention reduced the risk of contracting COVID-19 by 0.9 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 111. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high certainty evidence.


Contracting severe COVID-19 (measured at least 7 days after the second injection with a median follow-up of 3 months)

The relative risk of contracting severe COVID-19 in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 0.07 (95% CI 0.01 to 0.54). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 93%, compared with control vaccine.

There were only 9 events out of 15159 in the placebo group of the trial and no events in the group that received the vaccine.


Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Novavax COVID-19 vaccine versus placebo vaccine

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate certainty evidence.

Mortality

The existing evidence does not allow to assess the impact of Novavax COVID‑19 Vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to COVID-19 would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (>65y)

The relative risk of contracting COVID-19 (>65y) in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 0.11 (95% CI 0.01 to 0.88). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine reduced the risk of contracting COVID-19 (>65y) by 89%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (>65y). Comparison: Novavax/Serum Institute of India (SII) COVID-19 vaccine versus control vaccine

In the available trial, 9 people not receiving Novavax/Serum Institute of India (SII) COVID-19 vaccine out of 1957 presented this outcome (46 per 10000) versus 1 out of 1953 in the group that did receive it (5 per 10000). In other words, 41 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.41%, or that the intervention reduced the risk of contracting COVID-19 (>65y) by 0.41 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 244. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19 (<65y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate.

Contracting COVID-19 (12-18y)

The relative risk of contracting COVID-19 (12-18y) in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 0.21 (95% CI 0.08 to 0.55). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine reduced the risk of contracting COVID-19 (12-18y) by 79%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (12-18y). Comparison: Novavax/Serum Institute of India (SII) COVID-19 vaccine versus control vaccine

In the available trial, 14 people not receiving Novavax/Serum Institute of India (SII) COVID-19 vaccine out of 594 presented this outcome (236 per 10000) versus 6 out of 1205 in the group that did receive it (50 per 10000). In other words, 186 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.86%, or that the intervention reduced the risk of contracting COVID-19 (12-18y) by 1.86 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 54. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19 (12-18y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate.

Summary of findings table (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the 2019nCoV-302 trial was 48.6% (3411 out of 7020 participants) [Seth Toback, 2021 ].
Vaccine efficacy for this subgroup in the 2019nCoV-302 trial has not yet been reported [Seth Toback, 2021 ].
  
Age
Randomized trials
The proportion of participants 65 years of age and older in the 2019nCoV-302 was 27.9% (3910 out of 14039 participants) [Seth Toback, 2021 ].
The vaccine efficacy among participants ≥65 years was 88.9% (95% CI, 12.8 to 98.6) and efficacy from 14 days after dose 1 was 83.4% (95% CI, 73.6 to 89.5) [Seth Toback, 2021 ].
  
Children and adolescents
Randomized trials
The expansion for adolescents of the PREVENT-19 trial included 2,247 participants aged 12 to 18 years of age. Vaccine efficacy measured at least seven days after the second dose was 79% (95% CI, 45% to 92%). [Germán Áñez, 2022 ]

ICMR/SII-COVOVAX was a phase 2/3 randomized controlled trial conducted in India that assessed the immunogenicity and safety of Covovax in children aged 2 to 17 years old. 460 participants aged 2 to 11 years olds were randomized and received the first dose of the vaccine or placebo (345 and 115, respectively) and 445 received the second dose or placebo (333 and 112, respectively). Also, 346 participants aged 12 to 17 years old received Covovax, and 114 received placebo. After the second dose, there was more than a 84-fold rise in neutralizing antibodies GMTs from baseline in the participants who received Covovax. The GMTs in both age groups were non-inferior to those observed in Indian adults. [Bhagwat Gunale, 2023 ]
  
Pregnancy
Randomized trials
Pregnant females were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 
  
Breastfeeding
Randomized trials
The efficacy of the vaccine in breastfeeding females was not reported in the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 
  
Immunocompromised persons
Randomized trials
Immunocompromised persons were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 
  
Persons living with HIV were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 

Post hoc vaccine efficacy analysis against B.1.351 variant was 51.0% (95% CI, −0.6 to 76.2) among the HIV-negative participants [Shinde V, 2021 ].

In the phase 2a/b 2019nCoV-501 trial, out of 2,684 baseline seronegative participants (94% HIV negative and 6% HIV positive), 15 participants in the vaccine group and 29 in the placebo group developed mild to moderate Covid-19. The vaccine was 49.4% effective (95% CI 6.1 to 72.8). The efficacy of the vaccine among HIV negative participants was 60.1% (95% CI, 19.9 to 80.1) [Shinde V, 2021 ][Madhi SA, 2022 ]

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
PREVENT-19 was a phase 3 randomized trial that included 745 participants: 669 in the vaccine group and 76 in the placebo group. Analyses were conducted with the cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases and from 639 vaccine recipient non-cases. Vaccine efficacy was 75.7% (95% CI, 49.8% to 93.2%), 81.7% (95% CI, 66.3% to 93.2%), and 96.8% (95% CI, 88.3% to 99.3%) for vaccine recipients with nAb ID50 titers of 50, 100 and 7,230 IU/ml, respectively [Fong Y, 2023 ].

Contracting severe COVID-19
No studies reported or assessed this outcome

Transmission
No studies reported or assessed this outcome

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7)
Shen X et al. was a non-comparative study (neutralizing capacity from recipients' sera) carried out in the United States. The study included 15 COVID-19 convalescent individuals, 40 recipients of the Moderna vaccine and 28 recipients of the Novavax vaccine. In the study, SARS-CoV-2 variant B.1.1.7 was compared to the D614G variant in neutralization assays with serum samples from COVID-19 convalescent individuals, recipients of the Moderna mRNA-1273 vaccine and 28 recipients of the Novavax Spike protein nanoparticle vaccine NVX-CoV2373 (2 weeks post second inoculation). The study showed that the fold differences were statistically significant for both ID50 and ID80 for Novavax recipients. The fold difference in ID50 titers ranged from 0.85 to >20 for Novavax sera (IQR 1.5 to 3.0). The fold difference in ID80 titer ranged from 0.89 to 3.98 for Novavax sera (IQR 1.5 to 2.6) [Shen X, 2021 ].

Omicron (B.1.1.529.1) 
Choi et al was a cohort study conducted in South Korea that evaluated the immune response of a Novavax booster dose in 50 participants who had received a primary vaccination schedule with mRNA or adenoviral-vector vaccines or a primary schedule vaccination and a mRNA booster dose. The study assessed GMT of neutralizing antibodies three weeks after Novavax booster vaccination. The results against Omicron BA.1 were 262.50 (95% CI, 118.68- 580.60) as a third dose, 94.36 (95% CI, 43.61- 204.15) as a fourth dose in infection-naïve participants, and 693.88 (95% CI, 372.11- 1293.89) as a fourth dose in prior-infected individuals. Results against Omicron BA.5 were 282.21 (95% CI, 127.27- 625.78) as a third dose, 106.14 (95% CI, 70.29- 160.27) as a fourth dose in infectio-naïve participants and 671.83 (95% CI,  393.88-1,145.92) as a fourth dose in prior-infected participants. [Choi MJ, 2022 ]

Bhiman JN et al was a cohort study conducted in South Africa that included 77 participants, 29 vaccinated with 2 doses of Novavax and 48 participants vaccinated with 3 doses of Novavax. The study assessed the neutralizing activity of sera from Novavax-vaccinated individuals following the primary schedule and after a booster dose. Fourteen days after 2 doses of Novavax vaccine, Geometric Mean Titer (GMT) against the ancestral strain were 1,401, with an 8.1-, 41- and 30-fold reduction against Beta, Omicron BA.1 and BA.-5, respectively. The neutralizing antibody titers against the ancestral strain were boosted to a GMT of 10,862. A significant 10-,35- and 12-fold increase in titers against Beta, Omicron BA.1 and Omicron BA.4/BA.5, respectively, were observed when compared with the response after 2 doses. [Jinal Nomathemba Bhiman, 2022 ]

2019nCoV-101 was a phase 2 randomized, observer-blinded, placebo-controlled trial conducted in the United States and Australia. The study included a subset of healthy adult participants who received a 2-dose primary series followed by third and fourth doses of NVX-CoV2373 administered at 6-month intervals. All active booster vaccinations were administered at the same dose level as the primary vaccination series (0.5 mL containing 5 µg SARS-CoV-2 rS with 50 µg Matrix-M adjuvant) via intramuscular injection. The study assessed the antibody response against ancestral, BA.1 and BA.4-5 strains of SARS-CoV-2 in sera of individuals who received Novavax vaccines. Neutralizing antibody GMT after 2 doses against BA.1 were 35.2 (95% CI, 24.9-49.7) and 50.9 (95% CI, 33.2-78.1) against BA.4-5. After 3 doses GMT were 553.9 (95% CI, 343.9-892.1) and 1,036 (95% CI, 605.4-1,774) against BA.1 and BA.4-5, respectively. After 4 doses GMT were 674.9 (95% CI, 439.6-1,036) and 1,224 (95% CI, 811.9-1,846) against BA.1 and BA.4-5, respectively.  [Katia Alves, 2022 ]

Efficacy outcomes
Alpha (B.1.1.7)
2019nCoV-302 was a phase 3, randomized clinical trial conducted in the United Kingdom. 14,020 participants were recruited (7,020 vaccine group and 7,020 placebo group). The study evaluated the efficacy population, cases of virologically confirmed, symptomatic mild, moderate, or severe Covid-19 with an onset at least 7 days after the second dose. The results showed efficacy against symptomatic COVID-19 infection of 86.3% (95% CI 71.3 to 93.5) [Heath PT, 2021 ].

Beta (B.1.351)
2019nCoV-501 was a phase 2 a/b, randomized clinical trial conducted in South Africa. 4,387 participants were recruited (2,199 vaccine group and 2,188 placebo group). The study evaluated the vaccine efficacy against symptomatic Covid-19 at Least 7 days after the second dose. The results showed an effectiveness against symptomatic COVID-19 infection of 43.0% (95% CI 0 to 70.4) in HIV-negative and medically stable people living with HIV participants, and an efficacy of 51.0% (95% CI, -0.6 to 76.2) in HIV-negative participants. [Shinde V, 2021 ].

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
2019nCoV-101 is a phase 1/2 randomized trial (registered with the number NCT04368988 sponsored by Covavax that is being conducted in Australia and the United States. It was first registered in April 2020 and has enrolled 1419 healthy adults 18 to 59 years of age in the phase 1 component and 18 to 84 years of age in the phase 2 component that received different doses and schedules of the vaccine, with or without adjuvant in a 1:1:1:1:1 ratio. A secondary analysis of 379 participants who were randomized to receive a booster dose or placebo was carried out. The Serum IgG GMTs and neutralizing antibodies were measured at day 35 (after primary schedule), day 189 (pre booster) and day 217 (post booster). Serum IgG GMTs increased from day 189 to day 217, reflecting a postbooster increase of approximately 33.7-fold, additionally, MN50 assay GMTs increased approximately 95.6-fold between day 189 and day 217. [Mallory RM, 2022 ]

2019nCoV-101 was a phase 2 randomized, observer-blinded, placebo-controlled trial conducted in the United States and Australia. The study included a subset of healthy adult participants who received a 2-dose primary series followed by third and fourth doses of NVX-CoV2373 administered at 6-month intervals. All active booster vaccinations were administered at the same dose level as the primary vaccination series (0.5 mL containing 5 µg SARS-CoV-2 rS with 50 µg Matrix-M adjuvant) via intramuscular injection. The study assessed the antibody response against ancestral, BA.1 and BA.4-5 strains of SARS-CoV-2 in sera of individuals who received Novavax vaccines. Neutralizing antibody GMT after 3 doses were7,434 (95% CI, 5,358-10,314), 553.9 (95% CI, 343.9-892.1) and 1,036 (95% CI, 605.4-1,774) against the ancestral strain, BA.1 and BA.4-5, respectively. After 4 doses GMT were 4,367 (95% CI, 3,182-5,993), 674.9 (95% CI, 439.6-1,036) and 1,224 (95% CI, 811.9-1,846) against the ancestral strain, BA.1 and BA.4-5, respectively. [Katia Alves, 2022 ]

2019nCoV-307 was a phase 3 randomized trial conducted in United States that included data from 911 participants boosted with three different manufacturing lots of NVXCoV2373 COVID-19 vaccines: 298 from group 1, 303 from group 2 and 304 from group 3. This study assessed whether NVX-CoV2373 would induce similar responses when used as a heterologous or homologous booster. Geometric mean fold rise (day 29 vs baseline) was 4.0 (95% CI, 1.0-16.0) for homologous booster. Geometric mean fold rise (day 29 vs baseline) was 2.7 (95% CI, 2.3-3.2), 2.4 (95% CI, 1.9-2.9) and 2.7 (95% CI, 1.6-4.4) for participants with Pfizer, Moderna, and Janssen primary schedules, respectively. [Dunkle, L. M., 2023 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralising responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralising responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

Choi et al was a cohort study conducted in South Korea that evaluated the immune response of a Novavax booster dose in 50 participants who had received a primary vaccination schedule with mRNA or adenoviral-vector vaccines or a primary schedule vaccination and a mRNA booster dose. The study assessed GMT of neutralizing antibodies three weeks after Novavax booster vaccination. Results against the ancestral strain were 2,496.29 (95% CI, 668.86-9,316.52) as a third dose, 1,468.77 (95% CI, 873.08-2,470.87) as a fourth dose in infection-naïve individuals, and 5,297.97 (95% CI, 3,971.23-7,067.96) as a fourth dose in prior-infected individuals.  Results against Omicron BA.1 were 262.50 (95% CI, 118.68- 580.60) as a third dose, 94.36 (95% CI, 43.61-204.15) as a fourth dose in infection-naïve participants, and 693.88 (95% CI, 372.11-1,293.89) as a fourth dose in prior-infected individuals. Results against Omicron BA.5 were 282.21 (95% CI, 127.27-625.78) as a third dose, 106.14 (95% CI, 70.29-160.27) as a fourth dose in infection-naïve participants and 671.83 (95% CI, 393.88-1,145.92) as a fourth dose in prior-infected participants.  [Choi MJ, 2022 ]

Kulkarni P et al was a clinical trial conducted in India that included 369 participants who were primed with AstraZeneca (AZ) or Covaxin (BBV152). They were randomized to receive a homologous booster or a Novavax (NVX) booster, 92 in the AZ+NVX group, 93 in the AZ+AZ group, 91 in the BBV152+NVX group and 93 in the BBV152+BBV152 group. Neutralizing antibodies were assessed at baseline (day 1), day 29, day 91 and day 181 for immunogenicity assessments. The neutralizing antibody titers (GMT) at day 29 against the Wuhan strain were 3,963 (95% CI, 3,343.8-4,696.7) in the AZ+NVX group, 2,031.9 (95% CI, 1,690.6-2,442.1) in the AZ+AZ group, 2,848.1 (95% CI, 2,370-3,422.6) in the BBV152+NVX group and 515.6 (95% CI, 395.4-672.3) in the BBV152+BBV152 group. GMT of NAbs against Omicron BA.1 were 164.5 (95% CI, 105.9-255.6) in the AZ+NVX group, 86.9 (95% CI, 57.9-130.7) in the AZ+AZ group, 194.3 (95% CI, 120.4-313.4) in the BBV152+NVX group and 41.1 (95% CI, 27.8-60.8) in the BBV152+BBV152 group. [Kulkarni P, 2023 ]

2019nCoV-307 was a phase 3 randomized trial conducted in United States that included data from 911 participants boosted with three different manufacturing lots of NVXCoV2373 COVID-19 vaccines: 298 from group 1, 303 from group 2 and 304 from group 3. This study assessed whether NVX-CoV2373 would induce similar responses when used as a heterologous or homologous booster. Geometric mean fold rise (day 29 vs baseline) was 4.0 (95% CI, 1.0-16.0) for homologous booster. Geometric mean fold rise (day 29 vs baseline) was 2.7 (95% CI, 2.3-3.2), 2.4 (95% CI, 1.9-2.9) and 2.7 (95% CI, 1.6-4.4) for participants with Pfizer, Moderna and Janssen primary schedules, respectively. [Dunkle, L. M., 2023 ]

Safety of the vaccine

Safety of the vaccine in preclinical studies

Safety outcomes were not assessed in the animal studies available [Tian JH, 2021 ],[Guebre-Xabier M, 2020 ], [Matthew J Gorman, 2021 ].

Safety of the vaccine in clinical trials

Main safety outcomes of Novavax/Serum Institute of India (SII) COVID-19 vaccine

Key messages

Novavax/Serum Institute of India (SII) COVID-19 vaccine increases the risk of any adverse events.

Novavax/Serum Institute of India (SII) COVID-19 vaccine increases the risk of serious adverse events.

Any adverse event (from 1st dose until at least 28 days after the second dose )

The relative risk of any adverse event in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 1.17 (95% CI 1.05 to 1.3). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine increased the risk of any adverse event by 17%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event . Comparison: Novavax/Serum Institute of India (SII) COVID-19 vaccine versus control vaccine

In the available trial, 3016 people not receiving Novavax/Serum Institute of India (SII) COVID-19 vaccine out of 17473 presented this outcome (173 per 1000) versus 5189 out of 27448 in the group that did receive it (202 per 1000). In other words, 29 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 2.9%, or that the intervention increased the risk of any adverse event by 2.9 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 34. Which means that 83 people need to receive the vaccine for one of them to present any adverse event .


Serious adverse events (from 1st dose until at least 28 days after the second dose )

The relative risk of serious adverse events in the group that received Novavax/Serum Institute of India (SII) COVID-19 vaccine, versus the group that received control vaccine was 0.92 (95% CI 0.74 to 1.15). This means Novavax/Serum Institute of India (SII) COVID-19 vaccine reduced the risk of serious adverse events by 8%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Novavax/Serum Institute of India (SII) COVID-19 vaccine versus control vaccine

In the available trial, 135 people not receiving Novavax/Serum Institute of India (SII) COVID-19 vaccine out of 17423 presented this outcome (8 per 1000) versus 210 out of 27298 in the group that did receive it (7 per 1000). In other words, 1 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.1%, or that the intervention reduced the risk of serious adverse events by 0.1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 1000. Which means that 83 people need to receive the vaccine for one of them to present serious adverse events.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high certainty evidence.

Safety of the vaccine in subgroups

Any adverse events (12-18y)

Adverse events occurred with similar frequency in vaccine and placebo recipients (15.9% vs. 15.6%). Reports of severe AEs were similar across treatment groups. There were no episodes of anaphylaxis, vaccine-enhanced Covid-19, Guillain Barré syndrome, thrombosis with thrombocytopenia syndrome (TTS), or myocarditis/pericarditis were observed.

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the 2019nCoV-302 trial was 48.6% (6801 out of 14039 participants) [Seth Toback, 2021 ].
Vaccine safety for this subgroup in the 2019nCoV-302 trial has not yet been reported [Seth Toback, 2021 ].
  
Age
Randomized trials
In the phase 2 of the 2019nCoV-101 trial, the proportion of patients 60-84 years of age in the analysis was 45.4% (583 out of 1283 participants) and between 18-59 was 54.4% (700 out of 1283 participants) [Neil Formica, 2021 ].
Following second vaccination, the frequencies of local adverse events were higher among younger participants and lower among the 60 to 84 year old participants. Following first and second vaccination, the frequency of systemic adverse events was higher among 18-59 years of age participants and lower among 60-84 years of age participants. Fever was reported in less than 2% of vaccine recipients across both age groups [Neil Formica, 2021 ]. 
   
Children and adolescents
Randomized trials
Children and adolescents were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup. [Seth Toback, 2021 ]

ICMR/SII-COVOVAX was a phase 2/3 randomized controlled trial conducted in India that assessed immunogenicity and safety of Covovax vaccine in children aged 2 to 17 years old. 460 participants aged 2 to 11 years old were randomized and received the first dose of the vaccine or placebo (345 and 115, respectively) and 445 received the second dose or placebo (333 and 112, respectively). Also, 346 participants aged 12 to 17 years old received Covovax and 114 received placebo. In the 12-to-17-year age group, a total of 30 unsolicited adverse events were reported in 28 participants (8.1%) in the Covovax group and 12 adverse events in 6 participants (5.3%) in the placebo group. In the 2-to-11-year age group, a total of 49 unsolicited adverse evengts were reported in 39 participants (11.3%) in the Covovax group and 14 adverse events in 13 participants (11.3%) in the placebo group. [Bhagwat Gunale, 2023 ]

Pregnancy
Randomized trials
Pregnant females were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ].

Breast-feeding
Randomized trials
The efficacy of the vaccine in breastfeeding females was not reported in the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 
  
Immunocompromised persons
Randomized trials
Immunocompromised persons were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ].

Persons living with HIV were excluded from the 2019nCoV-302 phase 3 trial, so no data are available for this subgroup [Seth Toback, 2021 ]. 

In the phase 2 2019nCoV-501, there were no reported differences in safety among the clinical trial participants living with HIV. Available data are currently insufficient to evaluate safety for persons living with HIV who are not well controlled on therapy [Shinde V, 2021 ]. 

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies

No comparative study reported or evaluated this outcome.

Non-comparative studies

Lee K.M et al was a non-comparative study conducted in the United States. The study enrolled 39,129 participants aged 18 to 80 years old and investigated unexpected menstrual bleeding after SARS-CoV-2 vaccination using an exploratory, mixed-methods survey instrument intended to capture a wide range of responses from current and formerly menstruating adults, between April 7, 2021 and June 29, 2021. The study reported that 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change after being vaccinated [Lee, K. M., 2022 ].

 

Monitoring

WHO indicates that after a vaccine is approved for use, regulators conduct robust monitoring of efficacy, as well as monitoring of safety and risk minimization (pharmacovigilance) activities. They need to continually monitor the safety of the vaccine to ensure that the benefits of the vaccine continue to outweigh the risks. [WHO, 2022 ]

Regarding safety surveillance and monitoring, serious adverse events, anaphylaxis and other severe allergic reactions, Bell's palsy, cases of multisystem inflammatory syndrome, cases of COVID-19 after vaccination resulting in hospitalization or death should be identified and recorded.

Regarding the effectiveness of the vaccine, the following should be monitored:
− Efficacy of the vaccine over time and whether protection can be prolonged with booster doses.
− Studies to investigate whether this vaccine reduces the transmission and viral spread of SARS-CoV-2.
− Evaluation and notification of vaccine failures and information on viral sequences.

Regarding the subgroups of interest
− Prospective studies on the safety of the COVID-19 vaccine in pregnant and lactating females.
− Occasional controlled trials on the safety and security of vaccination in children under 18 years of age.
− Safety data from vaccination in immunosuppressed people, including patients living with HIV and autoimmune diseases.

To review more information on the topic [WHO, 2022 ],[World Health Organization, 2021 ], [Organización Mundial de la Salud, 2022 ]

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