Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Homologous and Heterologous Boosting of the Chadox1-S1-S COVID-19 Vaccine With the SCB-2019 Vaccine Candidate: A Randomized, Controlled, Phase 2 Study.

Background: Ongoing outbreaks of coronavirus disease 2019 (COVID-19) are driven by waning immunity following primary immunizations and emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies. It has been suggested that heterologous boosters could enhance and potentially maintain population immunity. Methods: We assessed the immunogenicity and reactogenicity of booster doses of different formulations of aluminium hydroxide-adjuvanted SCB-2019 vaccine (9 µg of SCB-2019, with or without CpG-1018 adjuvant, or 30 µg of SCB-2019 with CpG-1018) in Brazilian adults primed with ChAdOx1-S vector vaccine. S-protein antibodies and ACE2-binding inhibition were measured by enzyme-linked immunosorbent assay (ELISA) on days 1, 15, and 29. Participants self-reported solicited adverse events and reactions. Results: All SCB-2019 formulations increased S-protein ELISA antibodies and ACE2 binding inhibition to a greater extent than ChAdOx1-S. After 30 µg of SCB-2019 + CpG + aluminium hydroxide, titers against wild-type S-protein were significantly higher than after ChAdOx1-S on days 15 and 29, as were titers of neutralizing antibodies against the wild-type strain and Beta, Gamma, Delta, and Omicron variants. Boosting with SCB-2019 or ChAdOx1-S was well tolerated, with no vaccine-related serious or severe adverse events. Conclusions: Boosting ChAdOx1-S-primed adults with SCB-2019 induced higher levels of antibodies against a wild-type strain and SARS-CoV-2 variants than a homologous ChAdOx1-S booster, with the highest responses being with the 30-µg SCB-2019 + CpG + aluminium hydroxide formulation. Clinical Trials Registration: NCT05087368.

Persistence of the Immune Responses and Cross-Neutralizing Activity With Variants of Concern Following 2 Doses of Adjuvanted SCB-2019 Coronavirus Disease 2019 Vaccine.

BACKGROUND: We have previously reported the safety and immunogenicity 4 weeks after 2 doses of the Clover coronavirus disease 2019 (COVID-19) vaccine candidate, SCB-2019, a stabilized prefusion form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S-trimer). We now report persistence of antibodies up to 6 months after vaccination, and cross-neutralization titers against 3 variants of concern (VoCs). METHODS: In a phase 1 study, adult (18-54 years of age) and elderly (55-75 years of age) volunteers received 2 vaccinations 21 days apart with placebo or 3-, 9-, or 30-µg. We measured immunoglobulin G (IgG) antibodies against SCB-2019, angiotensin-converting enzyme 2 (ACE2) competitive binding antibodies, and neutralizing antibodies against wild-type SARS-CoV-2 (Wuhan-Hu-1) at days 101 and 184, and neutralizing antibodies against 3 VoCs, Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1), in day 36 sera. RESULTS: Titers waned from their peak at days 36-50, but SCB-2019 IgG antibodies, ACE2 competitive binding antibodies, and neutralizing antibodies against wild-type SARS-CoV-2 persisted at 25%-35% of their observed peak levels at day 184. Day 36 sera also demonstrated dose-dependent increases in neutralizing titers against the 3 VoCs. CONCLUSIONS: SCB-2019 dose-dependently induced immune responses against wild-type SARS-CoV-2, which persisted up to day 184. Neutralizing antibodies were cross-reactive against 3 of the most prevalent VoCs.

Persistent replication of severe acute respiratory syndrome coronavirus in human tubular kidney cells selects for adaptive mutations in the membrane protein.

Severe acute respiratory syndrome (SARS) is a systemic disease characterized by both lung pathology and widespread extrapulmonary virus dissemination causing multiple organ injuries. In this regard, renal dysfunction is an ominous sign in patients with SARS. Indeed, clusters of SARS coronavirus (SARS-CoV) particles have been detected in the cytoplasm of renal tubular epithelial cells in postmortem studies, explaining the presence of infectious virus in the urine of SARS patients. In order to investigate the potential SARS-CoV kidney tropism, we have evaluated the susceptibility of human renal cells of tubular and glomerular origin to in vitro SARS-CoV infection. Immortalized cultures of differentiated proximal tubular epithelial cells (PTEC), glomerular mesangial cells (MC), and glomerular epithelial cells (podocytes) were found to express the SARS-CoV receptor angiotensin-converting enzyme 2 on their surface. Productive infection, however, occurred only in PTEC but not in glomerular cells. A transient infection with poor virus production was observed in MC, whereas podocytes were not permissive to SARS-CoV infection. In contrast to the cytopathic infection of the Vero E6 cell line, SARS-CoV did not cause overt cytopathic effects in PTEC or MC. Of interest, PTEC, but not MC, maintained stable levels of SARS-CoV production in serial subcultures, suggesting a persistent state of infection. In this regard, a SARS-CoV variant with increased replication capacity in PTEC was selected after four serial subculture passages. This SARS-CoV variant acquired a single nonconservative amino acid change from glutamic acid (E) to alanine (A) at position 11 in the viral membrane (M) protein. The E11A point mutation was sufficient for enhanced SARS-CoV replication and persistence in PTEC when introduced in a SARS-CoV recombinant infectious clone. These findings indicate that human PTEC may represent a site of SARS-CoV productive and persistent replication favoring the emergence of viral variants with increased replication capacity, at least in these kidney cells.