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

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Abstract

<div class="section"> <a class="named-anchor" id="d12391388e437">  </a> <h5 class="section-title" id="d12391388e438">Background</h5> <p id="d12391388e440">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. </p> </div><div class="section"> <a class="named-anchor" id="d12391388e442">  </a> <h5 class="section-title" id="d12391388e443">Method</h5> <p id="d12391388e445">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. </p> </div><div class="section"> <a class="named-anchor" id="d12391388e447">  </a> <h5 class="section-title" id="d12391388e448">Findings</h5> <p id="d12391388e450">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. </p> </div><div class="section"> <a class="named-anchor" id="d12391388e452">  </a> <h5 class="section-title" id="d12391388e453">Conclusions</h5> <p id="d12391388e455">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. </p> </div><div class="section"> <a class="named-anchor" id="d12391388e457">  </a> <h5 class="section-title" id="d12391388e458">Trial registry</h5> <p id="d12391388e460">https://rpcec.sld.cu/trials/RPCEC00000347</p> </div><div class="section"> <a class="named-anchor" id="d12391388e462">  </a> <h5 class="section-title" id="d12391388e463">Funding</h5> <p id="d12391388e465">: Supported by Finlay Vaccine Institute, BioCubaFarma and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20). </p> </div><div class="fig panel" id="undfig1"> <a class="named-anchor" id="undfig1">  </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/d16f7846-5a6a-4d45-bd9b-e302b7da81c8/PubMedCentral/image/fx1_lrg"/> </div> <div class="panel-content"/> </div><p id="d12391388e475"> <div class="list"> <a class="named-anchor" id="ulist0010">  </a> <ul class="so-custom-list" style="list-style-type: none"> <li id="u0010"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0010">Heterologous schedule was well tolerated in a cohort of 810 adults aged 19-80 years</p> </div> </li> <li id="u0015"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0015">Specific IgG and neutralizing antibody response were observed after vaccination</p> </div> </li> <li id="u0020"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0020">Neutralizing GMT vs D614G variant persisted after 7-8 months of vaccination</p> </div> </li> <li id="u0025"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0025">Serum samples of vaccinees neutralized VOCs alpha, beta, delta and omicron</p> </div> </li> </ul> </div> </p><p class="first" id="d12391388e498">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. </p>

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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.