Anhui Zhifei Longcom COVID-19 vaccine

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Extended version of the vaccine

Anhui Zhifei Longcom 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.

China's National Medical Products Administration
Authorized on 17 March 2021 [China's National Medical Products Administration, 2021 ].
Conditional marketing authorization for individuals 18 years of age and older.

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)
Authorized for emergency use on 12 January 2022 [INVIMA, 2022 ].

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

U.S. Food and Drug Administration (FDA)
Not authorized.

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
Indonesia
Uzbekistan

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

Manufacturing

Manufacturer
Anhui Zhifei Longcom Biopharmaceutical Co.Ltd., China. Sponsor of the vaccine clinical trials and main manufacturer [Business Insider, 2021 ].

Other manufacturers
Not described.

General characteristics

The Anhui Zhifei Longcom COVID-19 vaccine is an adjuvanted protein subunit COVID-19 vaccine. The protein subunit vaccine targets the receptor-binding domain (RBD) for SARS-CoV-2 located at C-terminal domain of S1 subunit in S protein (between R319 to K537) [An Y, 2021 ].

The protein was engineered as a tandem-repeat dimeric RBD to increase immunogenicity. Compared to the traditional monomeric RBD, RBD-dimer enhances the SARS-CoV-2 neutralizing antibodies [Dai L, 2020 ].

RBD is considered an attractive coronavirus vaccine target, because it focuses in the antibody response to block the receptor binding, therefore, poses low potential for antibody-dependent enhancement risk [Dai L, 2020 ].

The construct of RBD-dimer is produced in clinical-grade Chinese hamster ovary (CHO) cell lines and then formulated with aluminum hydroxide as an adjuvant, resulting in the final vaccine product [An Y, 2021 ].

 

Ingredients

Active ingredient
Recombinant SARS-CoV-2 RBD protein 25 μg

Excipients
Aluminum hydroxide adjuvant 0.25 mg
Sodium chloride
Disodium phosphate
L-Histidine

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

Anhui Zhifei Longcom COVID-19 vaccine is administered as a series of three doses (0.5 mL each) 4 and 8 weeks apart.

The pharmaceutical form is a suspension for intramuscular injection.
The preferred site of injection is the deltoid muscle of the upper arm.

If the administration of the second or third dose is inadvertently delayed it should be given as soon as possible, according to the manufacturer’s instructions.


Booster dose
Current recommendations do not suggest that individuals receive more than three doses of the Anhui Zhifei Longcom COVID-19 vaccine.


Heterologous COVID-19 vaccine schedules
Individuals starting a series with the Anhui Zhifei Longcom COVID-19 vaccine must complete the series with the same product.
There is no available data to support the interchangeability between the Anhui Zhifei Longcom COVID-19 vaccine and other vaccines against COVID-19.


Vaccination schedule for immunocompromised persons [INVIMA, 2022 ]
INVIMA (Colombia) recommends a primary series of three doses (0.5 mL each) provided 4 and 8 weeks apart.

Indications and contraindications

Indications

Anhui Zhifei Longcom COVID-19 vaccine is indicated for individuals from 18 to 59 years of age [Yang S, 2021 ].

Contraindications

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

The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of Anhui Zhifei Longcom COVID-19 vaccine.

Pregnancy
The available data on Anhui Zhifei Longcom COVID-19 vaccine is insufficient to assess vaccine efficacy in pregnancy since no clinical trials have included pregnant women [INVIMA, 2022 ].

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.

Pregnancy and breastfeeding
The available data on Anhui Zhifei Longcom COVID-19 vaccine is insufficient to assess vaccine efficacy in pregnancy and breastfeeding since no clinical trials have included pregnant or breastfeeding women [INVIMA, 2022 ].

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.

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.
WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination.
Administer with precaution in persons with epilepsy or progressive neurological disorders [INVIMA, 2022 ].

Co-administration with other vaccines
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.











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.

Storage and logistics

Storage

Anhui Zhifei Longcom COVID-19 vaccine is provided as a suspension stored at 5°C/41°F (between 2°C to 8°C [35°F to 46°F])[Yang S, 2021 ].

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.
Shake the vial gently.

Storage after first puncture

After the first puncture of the vial, preferably use immediately.
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

Randomized trials
NCV-Ⅰ-healthy is a phase 1 randomized trial (registered with the number NCT04466085 [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2020 ]) sponsored by Anhui Zhifei Longcom Biopharmaceutical that is being conducted in China [Yang S, 2021 ]. It was first registered in June 2020 and has enrolled 50 healthy adults aged 18–59 years that received three doses of the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart in a 2:2:1 ratio. It is expected to run until September 2021. The first report of outcome data published in a scientific journal was released in March 2021.
  
NCV-Ⅱ-healthy is a phase 2 randomized trial (registered with the number NCT04466085 [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2020 ]) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. that is being conducted in China [Yang S, 2021 ]. It was first registered in July 2020 and has enrolled 900 healthy people aged 18 to 59 years that received the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule in a 1:1:1:1:1:1 ratio. It is expected to run until December 2021. The first report of outcome data published in a scientific journal was released in March 2021.
   
LKM-2020-NCV-GJ01 was a phase-3 randomized trial (registered with the number NCT04646590) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. It included 28,873 adult participants (≥18 years of age) from 31 clinical centers across Uzbekistan, Indonesia, Pakistan, and Ecuador between 12 December 2020, and 15 December 2021. An additional center in China was included for the safety analysis. Participants were randomized to receive three injections of ZF2001 or placebo 30 days apart [Dai L, 2022 ].

Other studies providing efficacy or safety data
LKM-2021-NCV-JQ01 is an ongoing phase 1/2 non-randomized study (registered with the number NCT05198063) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2022 ]. It was first registered in January 2022 and plans to enroll 300 adults 18 years old and over who have completed the primary vaccination series of Anhui Zhifei Longcom COVID-19 vaccine.Those participants will receive a booster dose of the vaccine 6 months after the primary vaccination series. It is expected to run for until July 2022.
LKM-2021-NCV-JQ02 is an ongoing phase 1/2 non-randomized study (registered with the number NCT05198102) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021 ]. It was first registered in January 2022 and plans to enroll 300 adults 18 years old and over who have completed the primary vaccination series of Anhui Zhifei Longcom COVID-19 vaccine. Those participants will receive a booster dose of the vaccine 12 months after the primary vaccination series.  It is expected to run for until July 2022.
IIT-LKM-2021-NCV03-02 is an ongoing phase 1/2 non-randomized study (registered with the number  NCT05205096 [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021 ]) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. that is being conducted in China. It was first registered in January 2022 and plans to enroll 480 adults 18 years old and over who have completed the primary vaccination series of Sinovac COVID-19 vaccine. Those participants will receive a booster dose of Anhui Zhifei Longcom COVID-19 vaccine 3-9 months after the primary vaccination series. It is expected to run until June 2022.
IIT-LKM-2021-NCV03-01 is an ongoing phase 1/2 non-randomized study (registered with the number NCT05205083 [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021 ]) sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. that is being conducted in China. It was first registered in January 2022 and plans to enroll 480 adults 18 years old and over who have completed the primary vaccination series of Sinopharm/BIBP COVID-19 vaccine. Those participants will receive a booster dose of Anhui Zhifei Longcom COVID-19 vaccine 3-9 months after the primary vaccination series. It is expected to run until July 2022.

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

The immunogenicity of the vaccine was evaluated in mice and nonhuman primates [An Y, 2021 ].

To study the immunogenicity, groups of BALB/c mice were vaccinated with two doses of 10 µg of the vaccine, 21 days apart. Mice receiving placebo (adjuvant only) were used as negative control. Serum samples from mice were collected at different time points after vaccination to monitor the duration of antibody responses. The geometric mean titer was 256 on day 35, after the second dose, the mean titers remained high until the last sample was taken at 140 days, suggesting that the humoral responses induced by the vaccine would be durable in time [An Y, 2021 ].

Young rhesus macaques were immunized with two doses of 25 μg or 50 μg vaccine intramuscularly, 21 days apart. Macaques that received a placebo were used as controls. The results showed that both doses elicited high levels of serological RBD-binding IgG and SARS-CoV-2 neutralizing antibodies after one or two immunizations [An Y, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

Combined analysis of NCV-Ⅱ-healthy and NCV-Ⅰ-healthyphase 1/2 trials. Phase 1 trial enrolled 50 participants that were assigned to receive three doses of placebo (n=10), the 25 µg vaccine (n=20), or the 50 µg vaccine (n=20). The mean age of participants was 32.6 years. Phase 2 trial enrolled 900 participants that were assigned to receive different schemes of vaccination. One group of participants was assigned to receive two doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150). While, the second group was assigned to receive three doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150). The mean age of participants was 43.5 years [Yang S, 2021 ].

In the phase 1 trial, the main immunogenicity outcome was measured with the serological RBD-binding IgG titres with ELISA test to assess antibody responses. Results showed that seroconversion rates, at day 30 after the second dose, reached 93% (14 of 15 participants) in the 25 µg group and 94% (17 of 18 participants) in the 50 µg group. The SARS-CoV-2-neutralising GMTs were 14% (95% CI 8-24.6) in the 25 µg group and 11.4% (95% CI 6.6-19.8) in the 50 µg group at day 30 after the second dose, and increased to 94.5% (95% CI 49.3-181.3) in the 25 µg group and 117.8% (95% CI 64.6-214.9) in the 50 µg group at day 7 after the third dose [Yang S, 2021 ].

In the two-dose groups in phase 2 of the trial, on day 14 after the third dose, seroconversion rates were 0% (none of 140) in the placebo group, 99% (143 of 144) in the 25 µg group and 97% (139 of 143) in the 50 µg group. The neutralizing GMTs for SARS-CoV-2, 14 days after the second dose were 17.7% (95% CI: 13.6-23) in the 25 µg group and 14% (95% CI : 10.8-18.3) in the 50 µg group. While in the group that received all three doses, the neutralizing GMTs of SARS-CoV-2 14 days later were 102.5% (95% CI: 81.8-128.5) in the group of 25 µg and 69% (95% CI 53-90) in the 50 µg group [Yang S, 2021 ].

Key messages

Anhui Zhifei Longcom COVID-19 vaccine reduces the risk of contracting COVID-19

Anhui Zhifei Longcom COVID-19 vaccine reduces the risk of contracting severe COVID-19

Main efficacy outcomes of Anhui Zhifei Longcom COVID-19 vaccine

Contracting COVID-19 (measured at least 14 days after the third dose)

The relative risk of Contracting COVID-19 in the group that received control vaccine, versus the group that received Anhui Zhifei Longcom COVID-19 vaccine was 0.27 (95% CI 0.23 to 0.32). This means Anhui Zhifei Longcom COVID-19 vaccine reduced the risk of contracting COVID-19 by 73%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Anhui Zhifei Longcom COVID-19 vaccine versus control vaccine


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 third dose)

The relative risk of contracting severe COVID-19 in the group that received control vaccine, versus the group that received Anhui Zhifei Longcom COVID-19 vaccine was 0.14 (95% CI 0.06 to 0.33). This means Anhui Zhifei Longcom COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 86%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Anhui Zhifei Longcom COVID-19 vaccine versus control vaccine

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

Mortality

The existing evidence does not allow to assess the impact of Anhui Zhifei Longcom 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.

Summary of findings table (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The differential efficacy of the vaccine in sex groups was not reported in the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ].
  
Age
Randomized trials
LKM-2020-NCV-GJ01 was a randomized, double-blind, placebo controlled, phase 3 trial, which investigate the efficacy and safety of ZF2001. Adult participants (≥18 years of age) were randomly assigned in a 1:1 ratio to receive a total of three 25-μg doses (30 days apart) of ZF2001 or placebo. A total of 28,873 participants received at least one dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who had completed the three-dose regimen, for whom there were approximately 6 months of follow-up data. Vaccine efficacy against symptomatic COVID-19 infection was 67.6% (95% CI 21.9 to 87.8), RR 0,32 (CI 95% 0,12-0,78).
.[Dai L, 2022 ]

Children and adolescents
Randomized trials
Children and adolescents were excluded from the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ], therefore no data are available for this subgroup.
  
Pregnancy
Randomized trials
Pregnant women were excluded from the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ], therefore no data are available for this subgroup.
 
Breastfeeding
Randomized trials
Breastfeeding women were excluded from the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ], therefore no data are available for this subgroup.
  
Immunocompromised persons
Randomized trials
Breastfeeding women were excluded from the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ], therefore no data are available for this subgroup.

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
Alpha (B.1.1.7)
Zhao X et al. carried out a non-comparative study (neutralizing capacity from recipients' sera) in China, which included 28 vaccine recipients. The study reported data from the participants' serum samples. The results showed that the neutralizing titer did not decline, but slightly increased (1.1 fold to WT, P > 0.05), against B.1.1.7-spike pseudovirus. [Xin Zhao, 2021 ].

Beta (B.1.351)
Huang B et al. conducted a comparative study (neutralizing capacity from recipients' sera) in China, which included 12 vaccine recipients. The study reported data from the participants' serum samples. The results showed that Beta variant does not escape the immunity induced by vaccine targeting S protein dimeric RBD (Anhui Zhifei Longcom). GMT decreased from 106.1 (95% CI 75.0 to 150.1) to 66.6 (95% CI 51.0 to 86.9) [Huang B, 2021 ].

Cao Y et al. conducted a comparative study (neutralizing capacity from recipients' sera) in China, which included 20 Anhui Zhifei Longcom vaccine volunteers. The study reported data from the participants' serum samples. Results demonstrated that individuals are capable of inducing highly diverse anti-RBD NAbs that react differently toward the B.1.351 variant. These enable Anhui Zhifei Longcom vaccinees to exhibit a two times higher tolerance to 501Y.V2 variants [Cao Y, 2021 ].

Delta (B.1.617.2)
Zhao X et al. carried out a non-comparative study (neutralizing capacity from recipients' sera) in China, which included 28 vaccine recipients. The study reported data from the participants' serum samples. The results showed that the variant with double mutations in RBD B.1.617.2 [Delta]-spike showed roughly equivalent sensitivity to ZF2001-elicited antisera as compared with pseudovirus expressing WTspike (-1.1 and -1.2 fold to WT, respectively; p > 0.05) [Xin Zhao, 2021 ].

Omicron (B.1.1.529)
Zhang Z et al. conducted a comparative study in China, which included 904 participants with two doses of CoronaVac, who received CanSino, Anhui Zhifei or CoronVac boosters. The results show that booster vaccination increased GMT of neutralizing antibodies 86 (95% CI: 59 to 127), 14 days after vaccination. [Zhe Zhang, 2022 ].

Zhong J et al was a comparative study conducted in China. The study included 150 participants with two doses of CoronaVac vaccine: 50 received a low-dose aerosolized Ad5-nCoV booster, 50 received a high-dose aerosolized Ad5- nCoV booster, 50 received homologous booster and 14 received the ZF2001 booster. This study assessed whether heterologous immunization with aerosol inhalation induces robust antibody immune response. Neutralizing antibodies (NAbs) against Omicron for participants with low dose aerosolized Ad5-nCoV booster was 115.8 (95% CI, 48.63–73.86), for participants with high-dose aerosolized Ad5- nCoV booster was 115.8 (95% CI, 88.57–151.3) and 4.32 (95% CI, 4.00–4.84) for participants who received homologous booster. The conventional virus neutralizing assay confirmed that Ad5-nCoV booster induced higher titer of neutralizing antibodies than ZF2001 booster (116.80 (95% CI, 84.51–161.5) vs 4.40 (95% CI, 4.00–4.83). [Zhong J, 2022 ]

Zhao X et al was a comparative study evaluating the immunogenic response in participants receiving ZF-2001. The study included 97 participants, 20 of them received each dose at 0-1-2 months, 9 participants at 0-1-3 months, 16 participants at 0-1-6 months, 20 received 2 doses of inactivated vaccine and a booster dose of ZF-2001, 16 participants received each dose of ZF-2001 at 0-1-3 months and the sera was obtained 4-7 months after the booster dose. The study assessed neutralizing antibody titers against the prototype virus and Omicron subvariants. The titers of neutralizing antibodies against BA.1 as GMT had a fold change to prototype of 14.1 (-18.5-fold) in the 0-1-2 group, 54.7 (-8.0-fold) in the 0-1-3 group, 438.3 (-5.8-fold) in the 0-1-6 group, 89.9 (-7.4-fold) in the heterologous booster group and 44.0 (-5.9-fold) in the 0-1-3 group at 4-7m. The titers of neutralizing antibodies against BA.4-5 variants as GMT had a fold change to prototype of 7.7 (-31.6-fold) in the 0-1-2 group, 24.5 (-23.4-fold) in the 0-1-3 group, 270 (-10.8-fold) in the 0-1-6 group, 30.8 (-19.4-fold) in the heterologous boost group, 16.7 (-12.6-fold) 0-1-3 group at 4-7 months. [Zhao X, 2022 ].

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
JSVCT115 was a phase 4 randomized trial in China that included 120 participants who received a primary CanSino vaccine and one or two Anhui Zhifei Longcom boosters. Live virus-neutralizing antibody titers against WT SARS-CoV-2 isolate were measured 14 days after booster injection. A heterologous booster dose with ZF001 induced a significantly higher neutralizing antibody against the SARS-CoV-2 wild-type virus compared with the baseline (day 28 after prime vaccination with CanSino). The 0-56 days group had the highest GMT after booster injection 80.8 IU/ml (95% CI, 53.1-122.9). All groups reached seroconversion in over 80% of the participants. Anti-RBD and anti-Spike IgG titers were highest for the 56-day + 6-month booster regime. The median of IFN-γ spot counts per 106 PBMCs 14 days after the first boost and second booster was comparable for the groups receiving boosters at 28 days, 56 days, and 5 months after primary vaccination [Jin P, 2022 ].

Vaccine efficacy and effectiveness for heterologous schedule

No studies reported or assessed this outcome.

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
JSVCT115 was a phase 4 randomized trial in China that included 120 participants who received a primary CanSino vaccine and one or two Anhui Zhifei Longcom boosters. Live virus-neutralizing antibody titers against wild type SARS-CoV-2 isolate were measured 14 days after booster injection. A heterologous booster dose with ZF001 induced a significantly higher neutralizing antibody against the SARS-CoV-2 wild-type virus compared with the baseline (day 28 after prime vaccination with CanSino).  The 0-56 days group had the highest GMT after booster injection 80.8 IU/ml (95% CI, 53.1-122.9). All groups reached seroconversion in over 80% of the participants. Anti-RBD and anti-Spike IgG titers were highest for the 56-day + 6-month booster regime. The median of IFN-γ spot counts per 106 PBMCs 14 days after the first boost and second booster was comparable for the groups receiving boosters at 28 days, 56 days, and 5 months after primary vaccination [Jin P, 2022 ].

Zhang Z et al. conducted a comparative study in China, which included 904 participants with two doses of CoronaVac, who received CanSino, Anhui Zhifei or CoronVac boosters. Antibody levels and pseudovirus-based neutralizing titers were measured before and 7, 14 and 28 days after the booster vaccination. Heterologous boosting with Cansino via different routes can elicit significantly higher binding antibody levels than the other two groups. The heterologous booster regimens elicited a higher neutralizing response against the Omicron variant than the homologous regimen. The median antibody fold-increase from baseline to day 14 of Anhui Zhifei Longcom booster was  120 (IQR: 42-360)  [Zhe Zhang, 2022 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Safety outcomes were not assessed in the animal studies available [An Y, 2021 ].

Safety of the vaccine in clinical trials

Main safety outcomes of the Anhui Zhifei Longcom COVID-19 vaccine

Key messages

Anhui Zhifei Longcom COVID-19 vaccine increases the risk of any adverse events.

Anhui Zhifei Longcom COVID-19 vaccine increases the risk of serious adverse events.

Any adverse event (30 days post vaccination)

The relative risk of any adverse event in the group that received Anhui Zhifei Longcom COVID-19 vaccine, versus the group that received control vaccine was 1.03 (95% CI 1 to 1.06). This means Anhui Zhifei Longcom COVID-19 vaccine increased the risk of any adverse event by 3%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event . Comparison: Anhui Zhifei Longcom COVID-19 vaccine versus control vaccine

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

Serious adverse events (mean follow up: 4.1 months)

The relative risk of serious adverse events in the group that received control vaccine, versus the group that received Anhui Zhifei Longcom COVID-19 vaccine was 0.82 (95% CI 0.69 to 0.97). This means Anhui Zhifei Longcom COVID-19 vaccine reduced the risk of serious adverse events by 18%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Anhui Zhifei Longcom COVID-19 vaccine versus control vaccine

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

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The differential safety of the vaccine in sex groups was not reported in the LKM-2020-NCV-GJ01 phase 3 trial [Dai L, 2022 ].
  
Age
Randomized trials
LKM-2020-NCV-GJ01 was a phase 3 randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of ZF2001. Adult participants (≥18 years of age) were randomized 1:1 to receive a total of three 25-μg doses (30 days apart) of ZF2001 or placebo. The primary outcome was the occurrence of symptomatic coronavirus disease 2019 (Covid-19). Participants recorded adverse events (solicited and unsolicited) that occurred 0 to 7 days after each inoculation. Reported at least one adverse event in the vaccine group (≥60 years) 28.6% participants and in the placebo group (≥60 years) 28.6% participants. [Dai L, 2022 ]
  
The differential safety of the vaccine across age groups was not reported in the NCV-Ⅰ-healthy phase 1 trial and the NCV-Ⅱ-healthy phase 2 trial [Yang S, 2021 ].
  
Children and adolescents
Children and adolescents were excluded from the LKM-2020-NCV-GJ01 phase 3 trial, therefore there is no available data for this subgroup [Dai L, 2022 ].
  
Pregnancy
Pregnant women were excluded from the LKM-2020-NCV-GJ01 phase 3 trial, therefore there is no available data for this subgroup [Dai L, 2022 ].
  
Breastfeeding
Breastfeeding women were excluded from the LKM-2020-NCV-GJ01 phase 3 trial, therefore there is no available data for this subgroup [Dai L, 2022 ].
  
Immunocompromised persons
Immunocompromised persons were excluded from the LKM-2020-NCV-GJ01 phase 3 trial, therefore there is no available data for this subgroup [Dai L, 2022 ].

Safety of the vaccine post-authorization

Post-authorization studies
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

[China's National Medical Products Administration, 2021] China's National Medical Products Administration. China approves new type of vaccine for emergency use against COVID-19. Press release - China Daily - 2021-03-17. 2021; China's National Medical Products Administration. China approves new type of vaccine for emergency use against COVID-19. Press release - China Daily - 2021-03-17. 2021;
[INVIMA, 2022] INVIMA. Comisión revisora sala especializada de moléculas nuevas, nuevas indicaciones y medicamentos biológicos. Acta No. 01 de 2022- Primera parte. 2022; INVIMA. Comisión revisora sala especializada de moléculas nuevas, nuevas indicaciones y medicamentos biológicos. Acta No. 01 de 2022- Primera parte. 2022;
[Business Insider, 2021] Business Insider. Another Chinese Covid-19 vaccine enters late-stage human trials with a plan to produce 300 million doses annually. News. 2021; Business Insider. Another Chinese Covid-19 vaccine enters late-stage human trials with a plan to produce 300 million doses annually. News. 2021;
[An Y, 2021] An Y, Li S, Jin X et al. A tandem-repeat dimeric RBD protein-based COVID-19 vaccine ZF2001 protects mice and nonhuman primates. bioRxiv. 2021; An Y, Li S, Jin X et al. A tandem-repeat dimeric RBD protein-based COVID-19 vaccine ZF2001 protects mice and nonhuman primates. bioRxiv. 2021;
[Dai L, 2020] Dai L, Zheng T, Xu K et al. A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS. Cell. 2020;182(3). Dai L, Zheng T, Xu K et al. A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS. Cell. 2020;182(3).
[Reche PA, 2014] Reche PA, Fernandez-Caldas E, Flower DR, Fridkis-Hareli M, Hoshino Y. Peptide-based immunotherapeutics and vaccines. Journal of immunology research. 2014;2014:256784. Reche PA, Fernandez-Caldas E, Flower DR, Fridkis-Hareli M, Hoshino Y. Peptide-based immunotherapeutics and vaccines. Journal of immunology research. 2014;2014:256784.
[Yang S, 2021] Yang S, Li Y, Dai L et al. Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. The Lancet. Infectio Yang S, Li Y, Dai L et al. Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. The Lancet. Infectio
[PAHO, 2020] PAHO. The Immunization Program in the Context of the COVID-19 Pandemic, 26 March 2020. PAHO/FPL/IM/COVID-19/20-0005. 2020; PAHO. The Immunization Program in the Context of the COVID-19 Pandemic, 26 March 2020. PAHO/FPL/IM/COVID-19/20-0005. 2020;
[WHO, 2021] WHO. COVID-19 vaccination: supply and logistics guidance: interim guidance, 12 February 2021. WHO/2019-nCoV/vaccine_deployment/logistics/2021.1. 2021; WHO. COVID-19 vaccination: supply and logistics guidance: interim guidance, 12 February 2021. WHO/2019-nCoV/vaccine_deployment/logistics/2021.1. 2021;
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2020] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Phase I Clinical Study of Recombinant Novel Coronavirus Vaccine (CHO Cells). clinicaltrials.gov. 2020; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Phase I Clinical Study of Recombinant Novel Coronavirus Vaccine (CHO Cells). clinicaltrials.gov. 2020;
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2020] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Clinical Study of Recombinant Novel Coronavirus Vaccine. clinicaltrials.gov. 2020; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Clinical Study of Recombinant Novel Coronavirus Vaccine. clinicaltrials.gov. 2020;
[Dai L, 2022] Dai L, Gao L, Tao L et al. Efficacy and Safety of the RBD-Dimer-Based Covid-19 Vaccine ZF2001 in Adults. The New England journal of medicine. 2022;386(22):2097-2111. Dai L, Gao L, Tao L et al. Efficacy and Safety of the RBD-Dimer-Based Covid-19 Vaccine ZF2001 in Adults. The New England journal of medicine. 2022;386(22):2097-2111.
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2022] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. ZF2001 Booster Immunization Clinical Trials of 6 Months After the Completion of Basic Immunization. clinicaltrials.gov. 2022; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. ZF2001 Booster Immunization Clinical Trials of 6 Months After the Completion of Basic Immunization. clinicaltrials.gov. 2022;
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. ZF2001 Booster Immunization Clinical Trials of 12 Months After the Completion of Basic Immunization. clinicaltrials.gov. 2021; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. ZF2001 Booster Immunization Clinical Trials of 12 Months After the Completion of Basic Immunization. clinicaltrials.gov. 2021;
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Immunogenicity and Safety of Booster Immunization of ZF2001 After Inoculation With Two Doses of CoronaVac. clinicaltrials.gov. 2021; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Immunogenicity and Safety of Booster Immunization of ZF2001 After Inoculation With Two Doses of CoronaVac. clinicaltrials.gov. 2021;
[Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd., 2021] Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Immunogenicity and Safety of Booster Immunization of ZF2001 After Inoculation With Two Doses of BBIBP-CorV. clinicaltrials.gov. 2021; Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.. Immunogenicity and Safety of Booster Immunization of ZF2001 After Inoculation With Two Doses of BBIBP-CorV. clinicaltrials.gov. 2021;
[The GRADE Working Group, 2013] The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. Schünemann H, Bro?ek J, Guyatt G, Oxman A, editors. 2013; The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. Schünemann H, Bro?ek J, Guyatt G, Oxman A, editors. 2013;
[Xin Zhao, 2021] Xin Zhao, Anqi Zheng, Dedong Li et al. Neutralization of recombinant RBD-subunit vaccine ZF2001-elicited antisera to SARS-CoV-2 variants including Delta. bioRxiv. 2021; Xin Zhao, Anqi Zheng, Dedong Li et al. Neutralization of recombinant RBD-subunit vaccine ZF2001-elicited antisera to SARS-CoV-2 variants including Delta. bioRxiv. 2021;
[Huang B, 2021] Huang B, Dai L, Wang H et al. Serum sample neutralisation of BBIBP-CorV and ZF2001 vaccines to SARS-CoV-2 501Y.V2. The Lancet. Microbe. 2021; Huang B, Dai L, Wang H et al. Serum sample neutralisation of BBIBP-CorV and ZF2001 vaccines to SARS-CoV-2 501Y.V2. The Lancet. Microbe. 2021;
[Cao Y, 2021] Cao Y, Yisimayi A, Bai Y et al. Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines. Cell research. 2021;31(7):732-741. Cao Y, Yisimayi A, Bai Y et al. Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines. Cell research. 2021;31(7):732-741.
[Zhe Zhang, 2022] Zhe Zhang, Shipo Wu, Yawei Liu et al. Aerosolized Ad5-nCoV booster vaccination elicited potent immune response against the SARS-CoV-2 Omicron variant after inactivated COVID-19 vaccine priming. medRxiv. 2022; Zhe Zhang, Shipo Wu, Yawei Liu et al. Aerosolized Ad5-nCoV booster vaccination elicited potent immune response against the SARS-CoV-2 Omicron variant after inactivated COVID-19 vaccine priming. medRxiv. 2022;
[Zhong J, 2022] Zhong J, Liu S, Cui T et al. Heterologous booster with inhaled Adenovirus vector COVID-19 vaccine generated more neutralizing antibodies against different SARS-CoV-2 variants. Emerging microbes & infections. 2022;:1-18. Zhong J, Liu S, Cui T et al. Heterologous booster with inhaled Adenovirus vector COVID-19 vaccine generated more neutralizing antibodies against different SARS-CoV-2 variants. Emerging microbes & infections. 2022;:1-18.
[Zhao X, 2022] Zhao X, Zhang R, Qiao S et al. Omicron SARS-CoV-2 Neutralization from Inactivated and ZF2001 Vaccines. The New England journal of medicine. 2022; Zhao X, Zhang R, Qiao S et al. Omicron SARS-CoV-2 Neutralization from Inactivated and ZF2001 Vaccines. The New England journal of medicine. 2022;
[Jin P, 2022] Jin P, Guo X, Chen W et al. Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial. PLoS medi Jin P, Guo X, Chen W et al. Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial. PLoS medi
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