Safety, Tolerability, and Immunogenicity of Booster Dose with MVC-COV1901 or MVC-COV1901-Beta SARS-CoV-2 Vaccine in Adults: A Phase I, Prospective, Randomized, Open-Labeled Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines based on variant strains have been in use as booster doses to update immunity against circulating variants. Here we present the results of a phase one prospective, randomized, and open-labeled trial to study the safety and immunogenicity of a booster dose consisting of a subunit vaccine based on the stabilized prefusion SARS-CoV-2 spike protein, MVC-COV1901, or its Beta version, MVC-COV1901-Beta. Participants aged ≥18 and <55 years who received two or three prior doses of MVC-COV1901 vaccines were enrolled and were to receive a booster dose of either 15 mcg of MVC-COV1901, 15 mcg, or 25 mcg of MVC-COV1901-Beta in a 1:1:1 ratio. Adverse reactions after either MVC-COV1901 or MVC-COV1901-Beta booster doses after two or three doses of MVC-COV1901 were comparable and mostly mild and transient. At four weeks after the booster dose, participants with two prior doses of MVC-COV1901 had higher levels of neutralizing antibodies against ancestral SARS-CoV-2, Beta, and Omicron variants than participants with three prior doses of MVC-COV1901, regardless of the type of booster used. MVC-COV1901 and MVC-COV1901-Beta can both be effectively used as booster doses against SARS-CoV-2, including the BA.4/BA.5 Omicron variants.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Medigen COVID-19 protein vaccine.

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including protein subunit vaccines. This article uses the BRAVATO template to review the features of the MVC-COV1901 vaccine, a recombinant protein subunit vaccine based on the stabilized pre-fusion SARS-CoV-2 spike protein S-2P, adjuvanted with CpG 1018 and aluminum hydroxide, manufactured by Medigen Vaccine Biologics Corporation in Taiwan. MVC-COV1901 vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12 years of age and older. The template offers details on basic vaccine information, target pathogen and population, characteristics of antigen and adjuvant, preclinical data, human safety and efficacy data, and overall benefit-risk assessment. The clinical development program began in September 2020 and based on demonstration of favorable safety and immunogenicity profiles in 11 clinical trials in over 5,000 participants, it has been approved for emergency use based on immunobridging results for adults in Taiwan, Estwatini, Somaliland, and Paraguay. The main clinical trials include placebo-controlled phase 2 studies in healthy adults (CT-COV-21), adolescents (CT-COV-22), and elderly population (CT-COV-23) as well as 3 immunobridging phase 3 trials (CT-COV-31, CT-COV-32, and CT-COV-34) in which MVC-COV1901 was compared to AZD1222. There are also clinical trials studying MVC-COV1901 as homologous and heterologous boosters (CT-COV-24 and CT-COV-25). The totality of evidence based on ∼3 million vaccinees to date includes a mostly clean safety profile, with adverse events mostly being mild and self-limiting in both clinical development and post-marketing experience, proven immunogenic response, and real-world effectiveness data. The immunogenic profile demonstrates that MVC-COV1901 induces high levels of neutralizing and binding antibodies against SARS-CoV-2. There is a dose-dependent response and a significant correlation between binding and neutralizing antibody activity. Antigen-specific T-cell responses, particularly a Th1-biased immune response characterized by high levels of interferon gamma and IL-2 cytokines, have also been observed. Coupled with this, MVC-COV1901 has favorable thermostability and better safety profiles when compared to other authorized vaccines from different platforms, which make it potentially a good candidate for vaccine supply chains in global markets.

Safety and immunogenicity of SARS-CoV-2 vaccine MVC-COV1901 in Taiwanese adolescents: a randomized phase 2 trial.

Adolescents and children play an important role in SARS-CoV-2 transmission and epidemiology. MVC-COV1901 is a subunit SARS-CoV-2 vaccine based on stabilized spike protein adjuvanted with CpG 1018 and aluminum hydroxide that has received emergency use approval (EUA) for adults in Taiwan. In this study, we have investigated the safety and immunogenicity of two doses of MVC-COV1901 in adolescents. Healthy adolescents from the age of 12-17 years were randomly assigned to receive two intramuscular doses of either MVC-COV1901 or placebo at 28 days apart. Adverse events were mostly mild and were similar in MVC-COV1901 and placebo groups, with the most commonly reported adverse events being pain/tenderness and malaise/fatigue. All immunogenicity endpoints in the adolescent group were non-inferior to the endpoints seen in the young adult and placebo groups. The results here advocate the use of MVC-COV1901 in adolescents in the ongoing efforts to control the pandemic.ClinicalTrials.gov registration: NCT04951388.

Protection of hamsters challenged with SARS-CoV-2 after two doses of MVC-COV1901 vaccine followed by a single intranasal booster with nanoemulsion adjuvanted S-2P vaccine.

Intramuscular vaccines have greatly reduced hospitalization and death due to severe COVID-19. However, most countries are experiencing a resurgence of infection driven predominantly by the Delta and Omicron variants of SARS-CoV-2. In response, booster dosing of COVID-19 vaccines has been implemented in many countries to address waning immunity and reduced protection against the variants. However, intramuscular boosting fails to elicit mucosal immunity and therefore does not solve the problem of persistent viral carriage and transmission, even in patients protected from severe disease. In this study, two doses of stabilized prefusion SARS-CoV-2 spike (S-2P)-based intramuscular vaccine adjuvanted with Alum/CpG1018, MVC-COV1901, were used as a primary vaccination series, followed by an intranasal booster vaccination with nanoemulsion (NE01)-adjuvanted S-2P vaccine in a hamster model to demonstrate immunogenicity and protection from viral challenge. Here we report that this vaccination regimen resulted not only in the induction of robust immunity and protection against weight loss and lung pathology following challenge with SARS-CoV-2, but also led to increased viral clearance from both upper and lower respiratory tracts. Our findings showed that intramuscular MVC-COV1901 vaccine followed by a booster with intranasal NE01-adjuvanted vaccine promotes protective immunity against both viral infection and disease, suggesting that this immunization protocol may offer a solution in addressing a significant, unmet medical need for both the COVID-19 and future pandemics.

Hamsters Protected from SARS-CoV-2 Delta Variant Challenge after Two Doses of Adjuvanted SARS-CoV-2 Recombinant Spike Protein (S-2P) and One Dose of Beta S-2P.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern negatively impact the effectiveness of vaccines. In this study, we challenge hamsters with the delta variant after 2- or 3-dose inoculations with SARS-CoV-2 vaccines constructed from stabilized prefusion spike proteins (S-2P) of Wuhan (W) and beta (B) variants. Compared to 3 doses of W S-2P, 2 doses of W S-2P followed by a third dose of B S-2P induced the highest neutralizing antibody titer against live SARS-CoV-2 virus and enhanced neutralization of omicron variant pseudovirus. Reduced lung live virus titer and pathology suggested that all vaccination regimens protect hamsters from SARS-CoV-2 delta variant challenge.

Prevalence and diversity of rotavirus A in pigs: Evidence for a possible reservoir in human infection.

BACKGROUND: Rotavirus A (RVA) are a group of diverse viruses causing acute gastroenteritis (AGE) in humans and animals. Zoonotic transmission is an important mechanism for rotavirus evolution and strain diversity in humans, but the extent of pigs as a major reservoir for human infection is not clear. METHODS AND FINDINGS: We have surveyed 153 pig farms across Taiwan with a total of 4588 porcine stool samples from three age groups from 2014 to 2017. Nursing piglets (less than one month of age) had higher detection rate for rotavirus than older age groups. Five VP7 (G) genotypes and 5 VP4 (P) genotypes were found in a total of 14 different G/P genotype combinations. In addition, porcine RVA strains had 2 NSP4 (E) genotypes and 3 VP6 (I) genotypes. A P[3]-like genotype was also discovered among strains collected in 2016 and 2017. CONCLUSIONS: Most of the genes from Taiwanese porcine strains clustered with each other and the lineages formed by these strains were distinct from the sequences of numerous regional variants or globally circulating porcine strains, suggesting an independent evolutionary history for Taiwanese rotavirus genotypes. The close relationship among porcine RVA strains and some unique porcine-like genotypes detected sporadically among human children in swine farms illustrates that pigs might serve as a reservoir for potential zoonotic transmission and novel genotype evolution in Taiwan's insular environment.

Evaluating the Neutralizing Ability of a CpG-Adjuvanted S-2P Subunit Vaccine Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern.

BACKGROUND: Variants of concern (VoCs) have the potential to diminish the neutralizing capacity of antibodies elicited by vaccines. MVC-COV1901 is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine consisting of recombinant prefusion stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminum hydroxide. We explored the effectiveness of MVC-COV1901 against the VoCs. METHODS: Serum samples were taken from rats and phase 1 clinical trial human subjects immunized with a low, medium, or high dose of MVC-COV1901. The neutralizing titers of serum antibodies were assayed with pseudoviruses coated with the SARS-CoV-2 spike protein of the wild-type (WT), D614G, Alpha, or Beta variants. RESULTS: Rats vaccinated twice with vaccine containing high doses of antigen retained high levels of neutralization activity against the Beta variant, albeit with a slight reduction compared to WT. After the third dose, neutralizing titers against the Beta variant were noticeably enhanced regardless of the amount of antigen used for immunization. In humans, vaccinated phase 1 subjects still showed appreciable neutralization abilities against the D614G, Alpha, and Beta variants, although neutralizing titers were significantly reduced against the Beta variant. CONCLUSIONS: Two doses of MVC-COV1901 were able to elicit neutralizing antibodies against SARS-CoV-2 variants with an overall tendency of inducing higher immune response at a higher dose level. The neutralizing titers to the Beta variant in rats and humans were lower than those for WT and the Alpha variant. An additional third dose in rats was able to partially compensate for the reduction in neutralization against the Beta variant. We have demonstrated that immunization with MVC-COV1901 was effective against VoCs.

CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge.

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19.

The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment. In developing a COVID-19 vaccine, we applied technology previously used for MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein, S-2P. To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of neutralizing antibodies in sera of immunized mice against pseudotyped lentivirus reporter or live wild-type SARS-CoV-2. In addition, the antibodies elicited were able to cross-neutralize pseudovirus containing the spike protein of the D614G variant, indicating the potential for broad spectrum protection. A marked Th1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens of S-2P combined with CpG 1018 alone or CpG 1018 with alum. These data support continued development of CHO-derived S-2P formulated with CpG 1018 and alum as a candidate vaccine to prevent COVID-19 disease.

Recombinant GII.P16-GII.2 Norovirus, Taiwan, 2016.

In Taiwan, acute gastroenteritis outbreaks caused by a new norovirus genotype GII.2 increased sharply toward the end of 2016. Unlike previous outbreaks, which often involved restaurants, GII.2 outbreaks mainly occurred in schools. Phylogenetic analysis indicates that these noroviruses are recombinant GII.P16-GII.2 strains.

Novel G9 rotavirus strains co-circulate in children and pigs, Taiwan.

Molecular epidemiologic studies collecting information of the spatiotemporal distribution of rotavirus VP7 (G) and VP4 (P) genotypes have shown evidence for the increasing global importance of genotype G9 rotaviruses in humans and pigs. Sequence comparison of the VP7 gene of G9 strains identified different lineages to prevail in the respective host species although some of these lineages appear to be shared among heterologous hosts providing evidence of interspecies transmission events. The majority of these events indicates the pig-to-human spillover, although a reverse route of transmission cannot be excluded either. In this study, new variants of G9 rotaviruses were identified in two children with diarrhea and numerous pigs in Taiwan. Whole genome sequence and phylogenetic analyses of selected strains showed close genetic relationship among porcine and human strains suggesting zoonotic origin of Taiwanese human G9 strains detected in 2014-2015. Although the identified human G9P[19] and G9P[13] rotaviruses represented minority strains, the repeated detection of porcine-like rotavirus strains in Taiwanese children over time justifies the continuation of synchronized strain surveillance in humans and domestic animals.