Finlay Institute of Vaccines COVID-19 vaccine

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Extended version of the vaccine

Finlay Institute of Vaccines COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

Not authorized.
Expression of interest under assessment [Last checked at WHO EUL official website on 7 July 2022].

European Commission (based upon the recommendation of the European Medicines Agency [EMA])
Not authorized.

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
Not authorized.

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)
SOBERANA 02
Authorized for emergency use on August 2021 [CECMED, 2021 ].
3 September 2021: For individuals between 2 and 18 years of age [CECMED, 2021 ].

SOBERANA 02 ST
Authorized for emergency use on August 2021 [CECMED, 2021 ].

SOBERANA PLUS
Authorized for emergency use on September 2021 [CECMED, 2021 ].

SOBERANA PLUS ST

Authorized for emergency use on August 2021 [CECMED, 2021 ].

U.S. Food and Drug Administration
Not authorized.

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

Authorization in jurisdictions in Latin America and the Caribbean
Nicaragua
Venezuela

Authorization in other jurisdictions
Iran

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

Manufacturing

Manufacturer
SOBERANA 02 [Instituto Finlay de Vacunas, 2021 ], [CECMED, 2021 ]

Purified Antigen Biological Material
Center of Molecular Immunology., Cuba.

Active ingredient
Finlay Vaccine Institute., Cuba.

Filling and Packaging
National Center for Biopreparations., Cuba.


SOBERANA 02 ST [CECMED, 2021 ]

Purified Antigen Biological Material
Center of Molecular Immunology., Cuba.

Active ingredient
Finlay Vaccine Institute., Cuba

Filling and Packaging
National Center for Biopreparations., Cuba.

SOBERANA PLUS [Finlay Institute of vaccines, 2021 ], [Finlay Vaccine Institute, 2021 ], [CECMED, 2021 ]

Active ingredient
Center of Molecular Immunology., Cuba.

Filling and Packaging
National Center for Biopreparations., Cuba.

SOBERANA PLUS ST [CECMED, 2021 ]

Active ingredient
Center of Molecular Immunology., Cuba.

Filling and Packaging
National Center for Biopreparations., Cuba.

Other manufacturers
BioCubaFarma, Cuba.
Pasteur Institute, Iran.

General characteristics

The Finlay Institute COVID-19 vaccine is a protein subunit vaccine composed of SARS-CoV-2 receptor binding domain (RBD) protein (sequence 319-541) produced by biotechnology in CHO cells, covalently conjugated to tetanus toxoid and absorbed in aluminum hydroxide gel. In Soberana 02, each unit of tetanus toxoid contains between 4 and 8 units of the SARS-CoV-2 protein [Instituto Finlay de Vacunas, 2021 ].

The SARS-CoV-2 RBD comprises 193 amino acid residues from Thr333 to Pro527, including RBM 438-506 that interacts directly with ACE2. It contains eight cysteines forming four disulfide bridges, three of these stabilizing the RBD core and one within the RBM [Lan J, 2020 ], [Valdes-Balbin Y, 2021 ].

In Soberana 02, recombinant RBD 319-541 was obtained in CHO-cells with intentionally extended sequence adding S-glycoprotein residues 527 through 541, in order to include an additional Cys538. The cysteine is usually connected to Cys590 in the S-glycoprotein. The extended sequence includes two N-glycosylation sites at residues Asn331 and Asn343 and two O-glycosylation sites at Thr323 and Ser325. The selected sequence results in an unpaired Cys538 intended to be used for chemical conjugation to the highly immunogenic carrier tetanus toxoid (TT) [Valdes-Balbin Y, 2021 ].

 

SOBERANA 02

Ingredients

The vaccine contains the following ingredients [Instituto Finlay de Vacunas, 2021 ], [CECMED, 2021 ]:

Active ingredient
25 µg of RBD-TT

Adjuvant
Aluminum hydroxide gel

Excipients
Thimerosal
Sodium Chloride
Disodium hydrogen phosphate
Sodium dihydrogen phosphate
Water for injection

 

SOBERANA 02 ST [CECMED, 2021 ]

Ingredients

The vaccine contains the following ingredients [CECMED, 2021 ]:

Active ingredient
25 µg of RBD-TT

Adjuvant
Aluminum hydroxide gel

Excipients
Sodium Chloride
Disodium hydrogen phosphate
Sodium dihydrogen phosphate
Water for injection

 

Soberana Plus

Ingredients

The vaccine contains the following ingredients [Finlay Institute of vaccines, 2021 ], [Finlay Vaccine Institute, 2021 ], [CECMED, 2021 ]:

Active ingredient
50 µg of Recombinant protein of the receptor-binding domain of the SARS-CoV-2 virus (Dimeric RBD)

Adjuvant
Aluminum hydroxide gel

Excipients
Thimerosal 0.05mg
Sodium Chloride 4.25mg
Disodium hydrogen phosphate 0.03mg
Sodium dihydrogen phosphate 0.02mg
Water for injection 0.5mL

 

Soberana Plus ST 

Ingredients

The vaccine contains the following ingredients [CECMED, 2021 ]:

Active ingredient
50 µg of Recombinant protein of the receptor-binding domain of the SARS-CoV-2 virus (Dimeric RBD).

Adjuvant
Aluminum hydroxide gel.

Excipients
Sodium Chloride 4.25mg
Disodium hydrogen phosphate 0.03mg
Sodium dihydrogen phosphate 0.02mg
Water for injection 0.5mL

Risk considerations

Peptide-based vaccines have theoretical advantages over traditional whole-organism and other platforms [Reche PA, 2014 ]. 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 ].

Among the advantages of a recombinant subunit, vaccine platforms are their safety, stability at temperatures from 2ºC to 8°C, and ease of development [Muhuri M, 2020 ].

Furthermore, the recombinant receptor-binding domain (RBD) exposes the immune system to the surface of the receptor-binding and camouflaged regions within the RBD. It is being studied that this RBD when conjugated with tetanus toxoid, exposed surface improves, increasing the level of neutralizing antibodies [Philip Brouwer, 2020 ], [Brouwer PJM, 2020 ], [Yuan M, 2020 ], [Zost SJ, 2020 ].

Dosing and schedule

SOBERANA 02 [Instituto Finlay de Vacunas, 2021 ], [CECMED, 2021 ]

SOBERANA 02 COVID-19 vaccine is administered as a series of two doses (0.5 mL) 28 days apart. The preferred site is the deltoid muscle.


SOBERANA 02 ST [CECMED, 2021 ]

SOBERANA 02 ST COVID-19 vaccine is administered as a series of two doses (0.5 mL) 28 days apart. The preferred site is the deltoid muscle.



SOBERANA PLUS [Finlay Vaccine Institute, 2021 ], [CECMED, 2021 ]

SOBERANA PLUS COVID-19 vaccine is administered as a single dose (0.5 mL) as a booster vaccine 28 days after a two-dose vaccine schedule with SOBERANA® 02 or SOBERANA® 02 ST. The preferred site is the deltoid muscle.


SOBERANA PLUS ST [CECMED, 2021 ]

SOBERANA PLUS ST COVID-19 vaccine is administered as a single dose (0.5 mL) as a booster vaccine 28 days after a two-dose vaccine schedule with SOBERANA® 02 or SOBERANA® 02 ST. The preferred site is the deltoid muscle.

Vaccine doses should not be administered at intervals less than these minimum intervals. Occasionally, it may be necessary to administer a dose before the scheduled time. In these cases, is recommended up to 4 days before the expected age or the interval between doses established.

If the interval between doses is prolonged, a new vaccine regimen does not need to be repeated.

In COVID-19 convalescent individuals, a dose of 0.5 mL of SOBERANA PLUS or SOBERANA PLUS ST will be administered 2 months after their medical discharge.

Indications and contraindications

Indications

SOBERANA 02 [Instituto Finlay de Vacunas, 2021 ], [CECMED, 2021 ].

SOBERANA 02 COVID-19 vaccine is indicated for individuals from 2 years of age and older.

SOBERANA 02 ST [CECMED, 2021 ].

SOBERANA 02 ST COVID-19 vaccine is indicated in individuals from 2 years of age and older.

SOBERANA PLUS [Finlay Vaccine Institute, 2021 ], [CECMED, 2021 ].

SOBERANA PLUS COVID-19 vaccine is indicated as a single dose as a booster vaccine after a two-dose vaccine schedule with SOBERANA® 02 or SOBERANA® 02 ST in individuals 2 years of age and older.
For COVID-19 convalescent persons (2 years of age and older) as a single dose.

SOBERANA PLUS ST [CECMED, 2021 ].

SOBERANA PLUS COVID-19 vaccine is indicated as a single dose as a booster vaccine after a two-dose vaccine schedule with SOBERANA® 02 or SOBERANA® 02 ST in individuals 2 years of age and older.
For COVID-19 convalescent persons (2 years of age and older) as a single dose.

Contraindications

The vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of vaccines (See the list of ingredients under 'General characteristics' in the extended version).

A subsequent dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to a previous dose.

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

Precautions

Allergic reactions
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed in health care settings where anaphylaxis can be immediately treated.

In general, persons with an immediate non-anaphylactic allergic reaction to the first dose should not receive additional doses unless recommended by a health professional with specialist expertise.

Pregnancy
The available data on SOBERANA 02, SOBERANA 02 ST, or SOBERANA PLUS vaccines is insufficient to assess vaccine efficacy in pregnancy since no clinical trials have included pregnant women.
The vaccine should only be given to pregnant women if the risks outweigh the benefit.

Breastfeeding
The available data on SOBERANA 02, SOBERANA 02 ST, or SOBERANA PLUS vaccines for breastfeeding women is insufficient to assess if there is any associated risk.

Persons with previous SARS-CoV-2 infection
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection.

Persons with current acute COVID-19
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 [PAHO, 2020 ].

Other precautions
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia.


Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection.

Co-administration with other vaccines
If the person has recently received tetanus vaccination, they must wait 30 days for the administration of SOBERANA® 02 [Instituto Finlay de Vacunas, 2021 ].

There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule until data on co-administration with other vaccines are available.

Storage and logistics

Storage

SOBERANA 02, SOBERANA 02 ST, SOBERANA PLUS, SOBERANA PLUS ST COVID-19 vaccines must be stored refrigerated between 2°C to 8°C [35° to 46°F] [Instituto Finlay de Vacunas, 2021 ], [CECMED, 2021 ], [CECMED, 2021 ], [Finlay Institute of vaccines, 2021 ], [Finlay Vaccine Institute, 2021 ], [CECMED, 2021 ].
Do not freeze.

Shelf-life

Soberana 02 and Soberana 02 ST: 6 months.
Soberana Plus and Soberana Plus ST: 4 months.

Administration logistics

Inspect the vial to be used.
The vial should be discarded if particles or differences are observed in the described appearance of the vaccine.
Gently shake the contents of the bulb before extracting each dose, Before withdrawing the dose, shake the vial gently to ensure correct homogeneity.

Storage after first puncture

After the first puncture of monodose vial, use immediately.
In the multidose vial, after the first puncture, protect from light.
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. Another option is to 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:
The IFV/COR/05, SOBERANA 01A trial (RPCEC00000338 [Finlay Vaccine Institute (IFV), 2020 ]), conducted in Cuba, started in October 2020, involved 60 volunteers between the ages of 19 and 59 who were randomized into three groups in a 1:1:1 ratio. The first group received SOBERANA Plus 50 (50 mcg of d-RBD plus N. meningitides outer membrane vesicles); the second group received SOBERANA Plus 50 mcg d-RBD (three doses), and the third group received SOBERANA Plus 25 mcg d-RDB (three doses). Group 1 was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or SOBERANA Plus-50 (heterologous schedule). [Sonia Perez-Rodriguez, 2021 ], [Pérez-Rodríguez S, 2022 ]

The IFV/COR/06 trial (RPCEC00000340 [Finlay Vaccine Institute (IFV), 2020 ]) was conducted in Cuba since November 2020 and included 40 healthy adults aged 19 to 59 years. Participants were randomly assigned in a 1:1 ratio to receive the SOBERANA 02 vaccine in a schedule of 2 doses of 15 µg or 25 µg on days 0 and 28. On day 56, half of the volunteers randomly assigned to each group received the third dose of SOBERANA 02 (homologous group) and half received SOBERANA Plus (50 µg d-RBD/alumina, heterologous group) [Maria Eugenia-Toledo-Romani, 2021 ], [Maria Eugenia Toledo-Romani, 2021 ], [María Eugenia Toledo Romaní; Meiby de la Caridad Rodríguez González, 2020 ], [Eugenia-Toledo-Romaní M, 2022 ]

Phase 1/2:
The IFV/COR/12 (RPCEC00000374 [Finlay Vaccine Institute (IFV), 2021 ]) trial was conducted in Cuba, starting in June 2021, and including 350 children from 3 to 18 years of age. Participants received two doses of FINLAY-FR-2 (SOBERANA 02) and the third heterologous dose of FINLAY-FR-1A (SOBERANA PLUS) on days 0, 28 and 56, respectively. [Puga-Gómez R, 2022 ]

Phase 2:
The IFV/COR/08 trial (RPCEC00000347 [Finlay Vaccine Institute (IFV), 2021 ]) was conducted in Cuba, starting in December 2020. It included 810 healthy adults aged 19 to 80 years who were randomly assigned in a 4:4:1 ratio to receive a vaccine or a placebo. The intervention was administered in two doses of SOBERANA 02 and one dose of SOBERANA Plus in the vaccine or placebo group, with intervals of 28 days. [Ochoa-Azze R, 2022 ], [Eugenia-Toledo-Romaní M, 2022 ]

The IFV/COR/11 trial (RPCEC00000366 [Finlay Vaccine Institute (FVI), 2021 ]) was conducted in Cuba and started in April 2021 including 450 adults between 19 and 78 years old. 20 participants (aged 60 to 78 years) were included in the open phase 2a and a single group received one dose of the SOBERANA Plus vaccine (50 μg). In phase 2b, 430 participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the Soberana Plus vaccine and a control [Ochoa-Azze R, 2022 ].

Phase 3:
The IFV/COR/09 trial (RPCEC00000354 [Finlay Vaccine Institute (IFV), 2021 ]) conducted in Cuba, initiated in March 2021, included 44,031 healthy volunteers aged 19 to 80 years who were randomly assigned in a 1:1:1 ratio into three groups to receive two doses of SOBERANA 02 (group A); two doses of SOBERANA 02 followed by a third dose of SOBERANA Plus (heterologous scheme, group B); and placebo (two doses) administered 28 days apart. [Toledo-Romani, M. E., 2022 ], [Maria Eugenia-Toledo-Romani, 2022 ], [Maria Eugenia Toledo-Romani, 2021 ].

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

Preclinical studies have shown its immunogenic effect in mice and rabbits. The candidate vaccine induced high antibody titers against RBD and with the ability to inhibit the interaction of RBD with its receptor ACE2, as well as to neutralize the live virus. Also, it demonstrated that a specific effector T cell response is induced against the virus [Valdes-Balbin Y, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

Low antibody production was detected after the first dose in all intervention groups. Anti-RBD seroconversion rates increased progressively according to the number of doses of vaccine applied to each subject. After the third dose, seroconversion was 100%, 94.4%, and 94.7% for the FINLAY-FR-1, FINLAY-FR-1A-50ug, and FINLAY-FR-1A25ug groups, respectively. All formulations produced a very high increase in anti-RBD antibodies after the second dose, with mean values higher than those at baseline (p <0.05) [Sonia Perez-Rodriguez, 2021 ].

SOBERANA PLUS was a randomized clinical trial (phase2b) that included 430 participants aged 19-78 years: 344 in vaccine group and 86 in the placebo group. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response. Successful immune response was considered if sVNT50 was at least 250; a value six times higher than the geometric mean of sVNT50 of the Cuban Convalescent Serum Panel (CCSP). Successful immune response was present in 289 (81%) of 358 participants immunised with FINLAY-FR-1A, versus only four (5%) of 81 in the control group (p<0·0001) and nine (13%) of 68 in the CCSP (p<0.0001). High titres of sVNT50 were detected on day 28 post-vaccination: the GMT of sVNT50 on day 28 represented a 21-times increase over the CCSP value (p<0·0001), a 51-times increase over the pre-vaccination value (p<0·0001) and a 45-times increase over the control group. A significant increase in RBD antibodies was detected after vaccination (median: 301·0 U/mL [103·0-819·2] 28 days post-vaccination). [Ochoa-Azze R, 2022 ]

Key messages

Finlay Institute COVID-19 vaccine reduces de risk of contracting COVID-19

Finlay Institute COVID-19 vaccine reduces de risk of contracting severe COVID-19


Main efficacy outcomes of Finlay Institute COVID-19 vaccine

Contracting COVID-19 (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in the group that received Finlay Institute COVID-19 vaccine versus the group that received placebo vaccine was 0.28 (95% CI 0.19 to 0.4). This means Finlay Institute COVID-19 vaccine reduced the risk of contracting COVID-19 by 72%, compared with placebo vaccine.

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

In the trial identified in this review, 136 people not receiving Finlay Institute COVID-19 vaccine out of 14285 presented this outcome (10 per 1000) versus 38 out of 14355 in the group that did receive it (3 per 1000). In other words,8 less to 6 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 0.7%, or that the intervention reduced the risk of contracting COVID-19 by 0.7 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 NNT is 143. Which means that 143 people need to receive the vaccine for one of them to not contracting 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 14 days after the second injection)

The relative risk of contracting severe COVID-19 in the group that received Finlay Institute COVID-19 vaccine versus the group that received placebo vaccine was 0.22 (95% CI 0.08 to 0.57). This means Finlay Institute COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 78%, compared with placebo vaccine.

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

In the trial identified in this review, 23 people not receiving Finlay Institute COVID-19 vaccine out of 14285 presented this outcome (16 per 10000) versus 5 out of 14355 in the group that did receive it (3 per 10000). In other words,15 less to 7 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 0.13%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.13 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 NNT is 769. Which means that 769 people need to receive the vaccine for one of them to not contracting severe COVID-19

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

Summary of findings table (iSoF)

61a0dbf7e3089d04ceba0e09


Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials 
IFV/COR/09 was a phase 3 randomized clinical trial conducted in Cuba. The aim of the study was to assess the efficacy and safety of two doses of Soberana 02 vaccine with a heterologous booster dose. The results showed that vaccine efficacy to prevent symptomatic COVID-19 disease (2 dose schedule) was 68% (95% CI 51.1% to 79.6%)  for females and 74% (95% CI 55.1% to 84.5%) for males [Maria Eugenia Toledo-Romani, 2021 ].

Age
Randomized trials 
IFV/COR/09 was a phase 3 randomized clinical trial conducted in Cuba. The aim of the study was to assess the efficacy and safety of two doses of Soberana 02 vaccine with a heterologous booster dose. The results showed that vaccine efficacy to prevent symptomatic COVID-19 disease (2 dose schedule) was 85%(95% CI 48.8% to 95.4%) for individuals ≥ 65 years and 68% (95% CI 55.1 to 77.9) for individuals ≥19 to 64 years [Maria Eugenia Toledo-Romani, 2021 ].

Children and adolescents
Randomized trials
The available data are insufficient to assess the vaccine efficacy in children and adolescents. No ongoing randomized clinical trials were identified

Other comparative studies
IFV/COR/12 was a phase 1/2 trial to evaluate the safety and immunogenicity of two doses of FINLAY-FR-2 (SOBERANA 02) and the third heterologous dose of FINLAY-FR-1A (SOBERANA PLUS) in 350 children (3 to 18 years old) in Cuba. Two doses of SOBERANA 02 elicited a humoral immune response similar to natural infection (seroconversion index was 27.8; the median anti-RBD IgG was 57.0 UA/mL); the third dose with SOBERANA PLUS increased the response in all children, similar to that achieved in vaccinated young adults (seroconversion index to 154.5; anti-RBD IgG titers also increased significantly [p<0.005] to 325.7 UA/mL). The GMT of neutralizing titers was 173.8 (CI 95%, 131.7-229.5) against Alpha, 142 (CI 95%, 101.3-198.9) against Delta, 24.8 (CI 95%, 16.8-36.6) against Beta and 99.2 (CI 95%, 67.8-145.4) against Omicron. [Puga-Gómez R, 2022 ]

Pregnancy
Randomized trials
The available data are insufficient to assess vaccine efficacy in the pregnancy subgroup. No ongoing randomized clinical trials were identified.

Breastfeeding
Randomized trials
The available data are insufficient to assess vaccine efficacy in the breastfeeding subgroup. No ongoing randomized clinical trials were identified.

Immunocompromised persons
Randomized trials
The available data are insufficient to assess vaccine efficacy in the immunocompromised subgroup. No ongoing randomized clinical trials were identified.

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
No studies reported or assessed this outcome

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
Delta (B.1.617.2)
IFV/COR/06 was an open label phase 1 trial to evaluate safety and immunogenicity of SOBERANA 02 in two formulations  (15 or 25 μg) in 40 subjects, 19-59 years old. IFV/COR/08 was an open label phase 2 clinical trial including 100 volunteers aged 19-80 years old, receiving two doses of SOBERANA 02 (25 μg). In both trials, half of volunteers were selected to receive a third dose of corresponding SOBERANA 02 and half received SOBERANA PLUS. The molecular neutralizing effect of anti-RBD IgG against phages displaying delta (δ)-RBD (L452R + T478K) compared to D614G-RBD was analyzed in 16 serum samples from individuals vaccinated with the heterologous scheme. mVNT50 GMT of 962.9 (95% CI, 670.1-1384) against phages displaying D614G-RBD and 384.1 (95% CI, 262-562.9) against δ-RBD phages, meaning a reduction of 2.5-fold the molecular neutralization capacity of the antibodies. [Eugenia-Toledo-Romaní M, 2022 ]

Effectiveness outcomes
No studies reported or assessed this outcome

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
IFV/COR/06 was an open label phase I clinical trial to evaluate safety and immunogenicity of SOBERANA 02 in two formulations  (15 or 25 μg) in 40 subjects aged 19-59 years old. IFV/COR/08 was an open label phase II clinical trial including 100 volunteers aged 19-80 years old, receiving two doses of SOBERANA 02 (25 μg). In both trials, half of volunteers were selected to receive a third dose of corresponding SOBERANA 02 and half received SOBERANA PLUS. The homologous third dose scheme showed a anti-RBD increase, on day 84 the median was 3.4 times higher than on day 56. Also showed an molecular neutralization titre (mVNT50) increased 3.6-fold compared to the second dose. The conventional virus neutralization titre (cVNT50) was evaluated pre-vaccination and 28 days after the second and third doses. There were no significant differences for GMT cVNT50. [Eugenia-Toledo-Romaní M, 2022 ]

Cellular Response
IFV/COR/06 was an open label phase I clinical trial to evaluate safety and immunogenicity of SOBERANA 02 in two formulations (15 or 25 μg) in 40 subjects aged 19-59 years old. IFV/COR/08 was an open label phase II clinical trial including 100 volunteers aged 19-80 years old, receiving two doses of SOBERANA 02 (25 μg). In both trials, half of volunteers were selected to receive a third dose of corresponding SOBERANA 02 and half received SOBERANA PLUS. RBD-specific T cell response was assessed by IFN-γ and IL-4 expression in peripheral blood mononuclear cell (PBMC) in a subset of participants, as an indicative of Th1 or Th2 profile. A significant increase of both IFN-γ producing cells (p < 0.005) and IL-4 producing cells although significant (p < 0.001) occurred after the third dose (day 84) with no differences between both alternative third doses (p > 0.99). [Eugenia-Toledo-Romaní M, 2022 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
No studies reported or assessed this outcome

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
Soberana 01A was a phase 1 randomized trial conducted in Cuba. The aim of the study was to assess the immunogenicity induced by three doses of the SOBERANA vaccine candidates.  Low antibody production was detected after the first dose in all intervention groups. Anti-RBD seroconversion rates increased progressively according to the number of doses of vaccine applied to each subject. After the third dose, seroconversion was 100%, 94.4%, and 94.7% for the FINLAY-FR-1, FINLAY-FR-1A-50ug, and FINLAY-FR-1A25ug groups, respectively. All formulations produced a very high increase in anti-RBD antibodies after the second dose, with mean values higher than those at baseline (p <0.05). [Sonia Perez-Rodriguez, 2021 ]
   
IFV/COR/06 was an open label phase I clinical trial to evaluate safety and immunogenicity of SOBERANA 02 in two formulations  (15 or 25 μg) in 40 subjects aged 19-59 years old. IFV/COR/08 was an open label phase II clinical trial including 100 volunteers aged 19-80 years old, receiving two doses of SOBERANA 02 (25 μg). In both trials, half of volunteers were selected to receive a third dose of corresponding SOBERANA 02 and half received SOBERANA PLUS. The heterologous third dose scheme showed a anti-RBD increase, on day 84 the median was 4.7 times higher than on day 56. It also showed a molecular neutralization titre (mVNT50) increased 5.7-fold compared to the second dose. The conventional virus neutralization titre (cVNT50) was evaluated pre-vaccination and 28 days after the second and third doses. There were no significant differences for GMT cVNT50. [Eugenia-Toledo-Romaní M, 2022 ]

Cellular Response
IFV/COR/06 was an open label phase I clinical trial to evaluate safety and immunogenicity of SOBERANA 02 in two formulations (15 or 25 μg) in 40 subjects aged 19-59 years old. IFV/COR/08 was an open label phase II clinical trial including 100 volunteers aged 19-80 years old, receiving two doses of SOBERANA 02 (25 μg). In both trials, half of volunteers were selected to receive a third dose of corresponding SOBERANA 02 and half received SOBERANA PLUS. RBD-specific T cell response was assessed by IFN-γ and IL-4 expression in peripheral blood mononuclear cell (PBMC) in a subset of participants, as an indicative of Th1 or Th2 profile. A significant increase of both IFN-γ producing cells (p < 0.005) and IL-4 producing cells although significant (p < 0.001) occurred after the third dose (day 84) with no differences between both alternative third doses (p > 0.99). [Eugenia-Toledo-Romaní M, 2022 ]

Efficacy Outcomes
IFV/COR/09 was a phase 3 randomized clinical trial conducted in Cuba. The aim of the study was to assess the efficacy and safety of two doses of Soberana 02 vaccine with a heterologous booster dose. The results showed that vaccine efficacy to prevent symptomatic COVID-19 disease after three doses of vaccines was 92.4% (95% CI, 86.9% to 95.6%). [Maria Eugenia Toledo-Romani, 2021 ]

Safety of the vaccine

Safety of the vaccine in preclinical studies

A repeated dose toxicity study was conducted. Results show that the candidate vaccine is safe. There were no signs of toxicity in the animals and the vaccine was well tolerated [Instituto Finlay de vacunas, 2021; ].

Safety of the vaccine in clinical trials

Any adverse event

There are no phase 3 randomized trials that have yet reported outcome data.

Serious adverse events

There are no phase 3 randomized trials that have yet reported outcome data.

Non-serious adverse events

There are no phase 3 randomized trials that have yet reported outcome data.

Safety of the vaccine in subgroups

Sex
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.

Age
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.

Children and adolescents
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.

Pregnancy
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.


Breastfeeding
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.

Immunocompromised persons
Randomized trials
There are no randomized trials that have yet reported safety data in this subgroup.

Safety of the vaccine post-authorization

Comparative studies

No comparative study reported or evaluated this outcome.

Non-comparative studies

None available

Monitoring

WHO recommends the following research and post-authorization monitoring activities:

Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell’s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.

Vaccine effectiveness
− Vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− Studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding.
− Assessment and reporting of vaccination failures and virus sequence information.

Subgroups
− Prospective studies on the safety of COVID-19 vaccine in pregnant and lactating females.
− Randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− Safety data on vaccination in immunocompromised people, including patients living with HIV and autoimmune disease.

Vaccination logistics
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− Safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− Stability of the vaccine under alternative cold-chain distribution and storage conditions.
− Effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− Interchangeability studies within and across COVID-19 vaccine platforms.

References

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