Development of a two-component recombinant vaccine for COVID-19.

Though COVID-19 as a public health emergency of international concern (PHEIC) was declared to be ended by the WHO, it continues to pose a significant threat to human society. Vaccination remains one of the most effective methods for preventing COVID-19. While most of the antigenic regions are found in the receptor binding domain (RBD), the N-terminal domain (NTD) of the S protein is another crucial region for inducing neutralizing antibodies (nAbs) against COVID-19. In the two-dose immunization experiment, female BALB/c mice were intramuscularly immunized with different ratios of RBD-Fc and NTD-Fc proteins, with a total protein dose of 8 μg per mouse. Mice were immunized on day 0 and boosted on day 7. In the sequential immunization experiment, groups of female BALB/c mice were immunized with two doses of the inactivated SARS-CoV-2 vaccine (prototype strain) on day 0 and 7. On day 28, mice were boosted with RBD-Fc, NTD-Fc, RBD-Fc/NTD-Fc (9:1), RBD-Fc/NTD-Fc (3:1), inactivated SARS-CoV-2 vaccine (protoype strain), inactivated SARS-CoV-2 vaccine (omicron strain), individually. The IgG antibodies were detected using ELISA, while the neutralizing antibodies were measured through a microneutralization assay utilizing both the prototype and omicron strains. The ELISPOT assays were performed to measure the secretion of IL-4 and IFN-γ, and the concentrations of secreted IL-2 and IL-10 in the supernatants were measured by ELISA. We have first developed a two-component recombinant vaccine for COVID-19 based on RBD-Fc and NTD-Fc proteins, with an optimal RBD-Fc/NTD-Fc ratio of 3:1. This novel two-component vaccine demonstrated the ability to induce durable and potent IgG antibodies, as well as the neutralizing antibodies in both the two-dose homologous and sequential vaccinations. Heterologous booster with this two-component vaccine could induce higher neutralizing antibody titers than the homologous group. Additionally, the vaccine elicited relatively balanced Th1- and Th2-cell immune responses. This novel two-component recombinant vaccine exhibits high immunogenicity and offers a potential booster strategy for COVID-19 vaccine development.

Sun YS ，Xu F ，Zhu HP ，Xia Y ，Li QM ，Luo YY ，Lu HJ ，Wu BB ，Wang Z ，Yao PP ，Zhou Z ... -  《Frontiers in Immunology》

Safety and immunogenicity of a modified mRNA-lipid nanoparticle vaccine candidate against COVID-19: Results from a phase 1, dose-escalation study.

Essink BJ ，Shapiro C ，Isidro MGD ，Bradley P ，Pragalos A ，Bloch M ，Santiaguel J ，Frias MV ，Miyakis S ，Alves de Mesquita M ，Berrè S ，Servais C ，Waugh N ，Hoffmann C ，Baba E ，Schönborn-Kellenberger O ，Wolz OO ，Koch SD ，Ganyani T ，Boutet P ，Mann P ，Mueller SO ，Ramanathan R ，Gaudinski MR ，Vanhoutte N ... -  《-》

Phase II study on the safety and immunogenicity of single-dose intramuscular or intranasal administration of the AVX/COVID-12 "Patria" recombinant Newcastle disease virus vaccine as a heterologous booster against COVID-19 in Mexico.

The global inequity in the distribution of COVID-19 vaccines underscores the urgent need for innovative and cost-effective vaccine technologies to address access disparities and implement local manufacturing capabilities. This is essential for achieving and sustaining widespread immunity, and for ensuring timely protection of vulnerable populations during future booster campaigns in lower- middle income countries (LMICs). To address this need, we conducted a phase II clinical trial to evaluate the safety and immunogenicity of the locally manufactured AVX/COVID-12 "Patria" (AVX) vaccine as a booster dose. The vaccine was administered either intramuscularly (IM) or intranasally (IN) to participants who had previously completed a vaccination regimen for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using adenoviral vector, inactivated virus, or mRNA-based vaccines. Participants with initial anti-spike IgG titers below 1,200 U/mL were included, allowing us to observe the booster effect induced by vaccination. Both IM and IN immunization with AVX were found to be safe and well-tolerated. The vaccine induced a significant (>2.5-fold) increase in neutralizing antibodies against the ancestral Wuhan strain and variants of concern (VOCs), including Alpha, Beta, Delta, and Omicron (BA.2 and BA.5). This immune response was further supported by increased cellular production of interferon-gamma (IFN-γ), demonstrating a robust and multifaceted immune reaction. The administration of AVX as a booster dose, whether through IM or IN routes, was safe and well-tolerated. The vaccine extended immune responses not only against the ancestral Wuhan-1 strain but also against various VOCs. Its ability to enhance preexisting immune responses suggests a potential contribution to expanding and sustaining herd immunity within the population.

López-Macías C ，Torres M ，Armenta-Copca B ，Wacher NH ，Castro-Castrezana L ，Colli-Domínguez AA ，Rivera-Hernández T ，Torres-Flores A ，Damián-Hernández M ，Ramírez-Martínez L ，la Rosa GP ，Rojas-Martínez O ，Suárez-Martínez A ，Peralta-Sánchez G ，Carranza C ，Juárez E ，Zamudio-Meza H ，Carreto-Binaghi LE ，Viettri M ，Romero-Rodríguez D ，Palencia A ，Reyna-Rosas E ，Márquez-García JE ，Sarfati-Mizrahi D ，Sun W ，Chagoya-Cortés HE ，Castro-Peralta F ，Palese P ，Krammer F ，García-Sastre A ，Lozano-Dubernard B ... -  《-》

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 μg or 6 μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The study's aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50 % neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N = 82, 95 % CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N = 83, 95 % CI 29·03-44·15), 18·85 (VAXZEVRIA; N = 82, 95 % CI 15·10-23·54), and for subjects age ≥ 60 years was 37·27 (COVIVAC 3 μg; N = 42, 95 % CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N = 40, 95 % CI 35·46-70·76), 16·11 (VAXZEVRIA; N = 40, 95 % CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95 % CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95 % CI 1·98-5·32) for subjects age ≥ 60 years. On day 197, the age-specific ratios were 1·11 (95 % CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0 %, COVIVAC 6 μg 23·2 %, VAXZEVRIA 31·2 %); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194.

Thiem VD ，Anh DD ，Ha VH ，Van Thom N ，Thang TC ，Mateus J ，Carreño JM ，Raghunandan R ，Huong NM ，Mercer LD ，Flores J ，Escarrega EA ，Raskin A ，Thai DH ，Van Be L ，Sette A ，Innis BL ，Krammer F ，Weiskopf D ... -  《-》

Intranasal booster with SARS-CoV-2 RBD protein fused to E. coli enterotoxin a subunit after primary mRNA vaccination in mice.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 led to the coronavirus infection diseases 2019 (COVID-19) pandemic, significantly impacting global public health and the economy. Numerous COVID-19 vaccines based on the receptor binding domain (RBD) of SARS-CoV-2 spike protein have been developed, utilizing various protein expression platforms and adjuvant systems. In a previous study, we reported using the direct fusion of the A subunit of type IIb E. coli heat-labile enterotoxin with the SARS-CoV-2 RBD protein (RBD-LTA) as an intranasal vaccine candidate (Hsieh et al., 2023). In this study, we investigated the effects of an intranasal booster of RBD-LTA/RBD mixture proteins after one or two doses of intramuscular bivalent BA.4/5 mRNA vaccination over 17 and 35 weeks. Our results indicate that the intranasal RBD-LTA/RBD mixture proteins booster maintains high levels of anti-RBD IgG and neutralizing antibodies, comparable to those elicited by a two-dose mRNA vaccination regimen. An additional RBD-LTA/RBD mixture proteins booster significantly increased antibody titers, demonstrating the potential of this approach for long-term immunity against SARS-CoV-2. Our findings suggest that combining primary mRNA vaccination with an intranasal RBD-LTA/RBD mixture proteins booster can effectively sustain antibody levels over extended periods, providing a promising strategy for long-term protection against SARS-CoV-2 and its variants.

Hsieh HC ，Chen CC ，Liu WC ，Wu SC ... -  《-》