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      Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults

      research-article
      Author(s): 1 , ∗ , 2 , 3 , 2 , 4 , 5 , ∗ , 4 , 6 , 4 , 6 , 6 , 6 , 7 , 7 , 7 , 8 , 8 , 9 , 9 , 3 , 2 , 4 , ∗∗∗ , 4 , 4 , 4 , 6 , 10 , 11 , 11 , 6 , 4 , ∗ , 12 , 4 , ∗ , 4 , ∗∗ , SOBERANA Research Group
      Publication date (Electronic):
      Journal: Med (New York, N.y.)
      Publisher: Elsevier Inc.
      Keywords: conjugate vaccine, heterologous schedule, COVID-19, recombinant RBD, phase IIb clinical trial

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          Abstract

          Background

          SOBERANA 02 have been evaluated in phase I and IIa studies comparing homologous vs. heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety and reactogenicity of SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults.

          Method

          Phase IIb was a parallel, multicenter, adaptive, double blind, randomized and placebo-controlled trial. Subjects (N=810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredient of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD IgG concentration. Secondary outcomes were safety, reactogenicity and neutralizing antibodies.

          Findings

          Seroconversion rate in vaccinees was 76.3 %after two doses, and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and VOCs alpha, beta, delta and omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE.

          Conclusions

          Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose.

          Trial registry

          https://rpcec.sld.cu/trials/RPCEC00000347

          Funding

          : Supported by Finlay Vaccine Institute, BioCubaFarma and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

          Graphical abstract

          Highlights

          • •

            Heterologous schedule was well tolerated in a cohort of 810 adults aged 19-80 years

          • •

            Specific IgG and neutralizing antibody response were observed after vaccination

          • •

            Neutralizing GMT vs D614G variant persisted after 7-8 months of vaccination

          • •

            Serum samples of vaccinees neutralized VOCs alpha, beta, delta and omicron

          Abstract

          Phase IIb of SOBERANA 02 vaccine candidate demonstrated its safety and immunogenicity in a two-dose or three-dose heterologous schedule with SOBERANA Plus in adults aged 19-80. Neutralizing antibodies against D614G were detected after 7-8 months. Neutralizing IgG antibodies were detected against D614G and VOCs alpha, beta, delta and omicron.

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          Most cited references32

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          Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

          David Khoury, Deborah Cromer, Arnold Reynaldi … (2021)
          Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
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            Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

            Pedro M. Folegatti, Katie J. Ewer, Parvinder K. Aley … (2021)
            Summary Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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              Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

              Pengfei Wang, Manoj S. Nair, Lihong Liu … (2021)
              The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Med (N Y)
                Journal ID (iso-abbrev): Med (N Y)
                Title: Med (New York, N.y.)
                Publisher: Elsevier Inc.
                ISSN (Print): 2666-6359
                ISSN (Electronic): 2666-6340
                Publication date PMC-release: 8 August 2022
                Publication date (Electronic): 8 August 2022
                Affiliations
                [1 ]“Pedro Kourí” Tropical Medicine Institute. Av “Novia del Mediodía”, Kv 6 1/2, La Lisa, Habana, 11400, Cuba
                [2 ]"19 de Abril" Polyclinic. Tulipan St. between Panorama y Oeste, Nuevo Vedado, Plaza de la Revolución, Havana 10400, Cuba
                [3 ]Clinic #1. 21 St. and 190, La Lisa. Havana, Cuba
                [4 ]Finlay Vaccine Institute. 21st Ave. N° 19810 between 198 and 200 St, Atabey, Playa, Havana, Cuba
                [5 ]Cybernetics, Mathematics and Physics Institute. 15th St. #55, Vedado, Plaza de la Revolución, Havana 10400, Cuba
                [6 ]Center of Molecular Immunology. 15th Ave. and 216 St, Siboney, Playa, Havana, Cuba
                [7 ]National Civil Defense Research Laboratory. San José de las Lajas, Mayabeque, Cuba
                [8 ]Centre for Immunoassays. 134 St. and 25, Cubanacán, Playa, Havana, 11600 Cuba
                [9 ]National Clinical Trials Coordinating Center. 5th Ave. and 62, Miramar, Playa, Havana, Cuba
                [10 ]Chengdu Olisynn Biotech. Co. Ltd., and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
                [11 ]Pasteur Institute of Iran. No. 69, Pasteur Ave., Tehran 1316943551, Islamic Republic of Iran
                [12 ]Laboratory of Synthetic and Biomolecular Chemistry, Faculty of Chemistry, University of Havana, Havana 10400, Cuba
                Author notes
                [∗∗∗ ]Lead contact, Corresponding author: Sonsire Fernandez-Castillo, Ph.D. Finlay Vaccine Institute. 21st Ave. N° 19810 between 198 and 200 St, Atabey, Playa, Havana, Cuba. E-mail:
                [∗∗ ]Corresponding author: Vicente Verez Bencomo, Ph.D. Finlay Vaccine Institute. 21st Ave. N° 19810 between 198 and 200 St, Atabey, Playa, Havana, Cuba. E-mail:
                [∗]

                METR, CVS, YVB, DGR and VVB contributed equally to this work.

                Article
                Publisher Item ID: S2666-6340(22)00320-8
                DOI: 10.1016/j.medj.2022.08.001
                PMC ID: 9359498
                PubMed ID: 35998623
                SO-VID: dfe2dab9-6428-4d28-8cc9-fa5f2e63d620
                Copyright © © 2022 Elsevier Inc.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 31 January 2022
                Date revision received : 17 May 2022
                Date accepted : 2 August 2022
                Categories
                Subject: Clinical Advances

                Keywords: conjugate vaccine,heterologous schedule,covid-19,recombinant rbd,phase iib clinical trial
                Data availability:
                Keywords: conjugate vaccine, heterologous schedule, covid-19, recombinant rbd, phase iib clinical trial

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