Safety and immunogenicity of homologous versus heterologous booster dose with AZD1222, mRNA-1273, or MVC-COV1901 SARS-CoV-2 vaccines in adults: An observer-blinded, multi-center, phase 2 randomized trial.

OBJECTIVES: To report the safety and immunogenicity profile of a protein subunit vaccine (MVC-COV1901) compared to AZD1222 and mRNA-1273 when given as a third (booster) dose to individuals who have completed different primary vaccine regimens. METHODS: Individuals were classified according to their primary vaccine regimens, including two-dose MVC-COV1901, AZD1222, or mRNA-1273. A third dose of either half-dose MVC-COV1901, full-dose MVC-COV1901, standard-dose AZD1222, half-dose mRNA-1273 was administered in a 1:1:1:1 treatment ratio to individuals with an interval range of 84-365 days after the second dose. Endpoints included safety, humoral immunogenicity, and cell-mediated immune response on trial days 15 and 29. Exploratory endpoint included testing against variants of concern (Omicron). RESULTS: Overall, 803 participants were randomized and boosted - 201 received half-dose MVC-COV1901, 196 received full-dose MVC-COV1901, 203 received AZD1222, and 203 received half-dose mRNA-1273. Reactogenicity was mild to moderate, and less in the MVC-COV1901 booster group. Heterologous boosting provided the best immunogenic response. Boosting with mRNA-1273 in MVC-COV1901 primed individuals induced the highest antibody titers, even against Omicron, and cell-mediated immune response. CONCLUSIONS: Overall, MVC-COV1901 as a booster showed the best safety profiles. MVC-COV1901 as a primary series, with either homologous or heterologous booster, elicited the highest immunogenic response. CLINICALTRIALS: gov registration NCT05197153.

Potential lessons from the Taiwan and New Zealand health responses to the COVID-19 pandemic.

Approaches to preventing or mitigating the impact of the COVID-19 pandemic have varied markedly between nations. We examined the approach up to August 2020 taken by two jurisdictions which had successfully eliminated COVID-19 by this time: Taiwan and New Zealand. Taiwan reported a lower COVID-19 incidence rate (20.7 cases per million) compared with NZ (278.0 per million). Extensive public health infrastructure established in Taiwan pre-COVID-19 enabled a fast coordinated response, particularly in the domains of early screening, effective methods for isolation/quarantine, digital technologies for identifying potential cases and mass mask use. This timely and vigorous response allowed Taiwan to avoid the national lockdown used by New Zealand. Many of Taiwan's pandemic control components could potentially be adopted by other jurisdictions.

An evaluation of the safety and immunogenicity of MVC-COV1901: Results of an interim analysis of a phase III, parallel group, randomized, double-blind, active-controlled immunobridging study in Paraguay.

BACKGROUND: Data from previous studies of the MVC-COV1901 vaccine, a subunit vaccine against SARS-CoV-2 based on the stable prefusion spike protein (S-2P) adjuvanted with CpG 1018 adjuvant and aluminum hydroxide, suggest that the vaccine is generally safe and elicits a good immune response in healthy adults and adolescents. By comparing with AZD1222, this study adds to the findings from previous trials and further evaluates the breadth of protection offered by MVC-COV1901. METHODS: In this phase 3, parallel group, randomized, double-blind, active-controlled trial conducted in 2 sites in Paraguay, we assigned adults aged 18-91 years in a 1:1 ratio to receive intramuscular doses of MVC-COV1901 or AZD1222 administered as scheduled in the clinical trial. Serum samples were collected on the day of vaccination and 14 days after the second dose. Primary and secondary safety and immunogenicity endpoints were assessed. In addition, other outcomes investigated were cross-reactive immunity against the Omicron strain and the induction of IgG subclasses. RESULTS: A total of 1,030 participants underwent randomization. Safety data was derived from this set while primary immunogenicity data involved a per-protocol immunogenicity (PPI) subset including 225 participants. Among the participants, 58% are seropositive at baseline. When compared against AZD1222, MVC-COV1901 exhibited superiority in terms of neutralizing antibody titers and non-inferiority in terms of seroconversion rates. Reactogenicity was generally mild and no serious adverse event was attributable to MVC-COV1901. Both vaccines have a Th1-biased response predominated by the production of IgG1 and IgG3 subclasses. Omicron-neutralizing titers were 44.5 times lower compared to wildtype-neutralizing titers among seronegative individuals at baseline. This fold-reduction was 3.0 times among the seropositive. CONCLUSION: Safety and immunogenicity data of MVC-COV1901 from the study in Paraguay confirm previous results. The previous infection coupled with vaccination of this vaccine may offer protection against the Omicron strain though its durability is still unknown.

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.

Early Prompt Response to COVID-19 in Taiwan: Comprehensive surveillance, decisive border control, and information technology support.

Since the COVID-19 outbreak was detected in Wuhan in December 2019 by the event-based surveillance of Taiwan Centers for Disease Control, Taiwan has been aligning risk management to policy planning with the assistance of comprehensive surveillance and regular rapid risk assessments. Taiwan Central Epidemic Command Center (CECC) promptly initiated stepwise border control for major cities and provinces in China, European and American countries, and eventually expanded it to the whole world in March 2020. With stringent quarantine measures, the early response not only successfully blocked the first wave of imported cases, but also slowed down subsequent large local outbreaks. Digital technologies including digital fencing and government database linkage were adopted to facilitate the application of public health interventions and data collection. The experience of Taiwan's prompt and comprehensive response at the early stage may contribute to the preparedness for the next disease X outbreak.

Transmission Dynamics and Effectiveness of Control Measures during COVID-19 Surge, Taiwan, April-August 2021.

An unprecedented surge of COVID-19 cases in Taiwan in May 2021 led the government to implement strict nationwide control measures beginning May 15. During the surge, the government was able to bring the epidemic under control without a complete lockdown despite the cumulative case count reaching >14,400 and >780 deaths. We investigated the effectiveness of the public health and social measures instituted by the Taiwan government by quantifying the change in the effective reproduction number, which is a summary measure of the ability of the pathogen to spread through the population. The control measures that were instituted reduced the effective reproduction number from 2.0-3.3 to 0.6-0.7. This decrease was correlated with changes in mobility patterns in Taiwan, demonstrating that public compliance, active case finding, and contact tracing were effective measures in preventing further spread of the disease.

Durability and Immunogenicity of Neutralizing Antibodies Response Against Omicron Variants After Three Doses of Subunit SARS-CoV-2 Vaccine MVC-COV1901: An Extension to an Open-Label, Dose-Escalation Phase 1 Study.

INTRODUCTION: MVC-COV1901 is a protein subunit COVID-19 vaccine based on the stable prefusion spike protein S-2P adjuvanted with CpG 1018 and aluminum hydroxide. Interim results of a phase 2 clinical trial demonstrated favorable safety profile and immunogenicity and the vaccine has been authorized for use in Taiwan. However, waning antibody levels after immunization and variants of concern (VoC) could negatively impact vaccine-induced neutralization of virus. In this extension to the phase 1 clinical study we investigated a three-dose regimen of MVC-COV1901 for durability of antibody levels and virus neutralization capacity, including neutralization of the Omicron variant. METHODS: Forty-five healthy adults from 20 to 49 years of age were divided into three groups of 15 participants receiving two doses of either low dose (LD), medium dose (MD), or high dose (HD) of MVC-COV1901. Six months after the second dose (day 209), a third MD dose of MVC-COV1901 was administered to the LD and MD groups and a HD dose was given to the HD group. Safety was followed for up to 28 days after the booster dose by monitoring incidences of adverse events (AE). Immunogenicity and antibody persistence for up to 6 months after the booster dose were assessed by neutralizing assay with the wild-type (Wuhan) SARS-CoV-2 virus. To examine the immunogenicity of booster dose against variants, neutralizing assays were carried out with the Alpha, Beta, and Delta variant viruses and the Omicron variant pseudovirus using samples from 4 weeks after the booster dose. RESULTS: Adverse reactions after the booster dose were mostly mild and comparable to that of the first two doses. Compared to day 209, neutralizing antibodies were increased by 10.3-28.9 times at 4 weeks after the booster. During the 6-month follow-up after the booster, the rate of decline of neutralizing antibody level was much less than that after the second dose. Three doses of MVC-COV1901 also improved antibody-mediated neutralization of Alpha, Beta, and Delta variants as well as the Omicron variant pseudovirus. CONCLUSION: Our data showed increased persistence of neutralizing antibodies and enhancement of immunogenicity against VoCs offered after a third dose of MVC-COV1901. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04487210.

A hospital-related outbreak of SARS-CoV-2 associated with variant Epsilon (B.1.429) in Taiwan: transmission potential and outbreak containment under intensified contact tracing, January-February 2021.

OBJECTIVES: A hospital-related cluster of 22 cases of coronavirus disease 2019 (COVID-19) occurred in Taiwan in January-February 2021. Rigorous control measures were introduced and could only be relaxed once the outbreak was declared over. Each day after the apparent outbreak end, we estimated the risk of future cases occurring in order to inform decision-making. METHODS: Probabilistic transmission networks were reconstructed, and transmission parameters (the reproduction number R and overdispersion parameter k) were estimated. The reporting delay during the outbreak was estimated (Scenario 1). In addition, a counterfactual scenario with less effective interventions characterized by a longer reporting delay was considered (Scenario 2). Each day, the risk of future cases was estimated under both scenarios. RESULTS: The values of R and k were estimated to be 1.30 ((95% credible interval (CI) 0.57-3.80) and 0.38 (95% CI 0.12-1.20), respectively. The mean reporting delays considered were 2.5 days (Scenario 1) and 7.8 days (Scenario 2). Following the final case, ttthe inferred probability of future cases occurring declined more quickly in Scenario 1 than Scenario 2. CONCLUSIONS: Rigorous control measures allowed the outbreak to be declared over quickly following outbreak containment. This highlights the need for effective interventions, not only to reduce cases during outbreaks but also to allow outbreaks to be declared over with confidence.

Taiwan's COVID-19 response: Timely case detection and quarantine, January to June 2020.

The coronavirus disease 2019 (COVID-19) pandemic has become severe threats to economic, societal, and healthcare systems. To analyze the epidemiological characteristics of the COVID-19 outbreak in Taiwan and evaluate the key interventions, we conducted a retrospective cohort study during January 17-June 30, 2020. As of June 30, the COVID-19 outbreak, including 447 laboratory-confirmed cases, was eliminated by mixed approaches: border control, enhanced surveillance, case detection with contact tracing, quarantine, and population-based interventions like face mask use. The improvement of median time from disease onset to notification (5 days [range -3 to 27] before March 1 to 1 day [range -8 to 22] after March 1) suggested the timeliness and comprehensiveness of surveillance and contact tracing. Travel restrictions with quarantine, resulting in fewer clusters, were also complementary to minimize disease spread. Under combined interventions, Taiwan successfully contained the COVID-19 spread within the country and minimized its impact on the society.

Comparison of Estimated Effectiveness of Case-Based and Population-Based Interventions on COVID-19 Containment in Taiwan.

Importance: Taiwan is one of the few countries with initial success in COVID-19 control without strict lockdown or school closure. The reasons remain to be fully elucidated. Objective: To compare and evaluate the effectiveness of case-based (including contact tracing and quarantine) and population-based (including social distancing and facial masking) interventions for COVID-19 in Taiwan. Design, Setting, and Participants: This comparative effectiveness study used a stochastic branching process model using COVID-19 epidemic data from Taiwan, an island nation of 23.6 million people, with no locally acquired cases of COVID-19 reported for 253 days between April and December 2020. Main Outcomes and Measures: Effective reproduction number of COVID-19 cases (the number of secondary cases generated by 1 primary case) and the probability of outbreak extinction (0 new cases within 20 generations). For model development and calibration, an estimation of the incubation period (interval from exposure to symptom onset), serial interval (time between symptom onset in an infector-infectee pair), and the statistical distribution of the number of any subsequent infections generated by 1 primary case was calculated. Results: This study analyzed data from 158 confirmed COVID-19 cases (median age, 45 years; interquartile range, 25-55 years; 84 men [53%]). An estimated 55% (95% credible interval [CrI], 41%-68%) of transmission events occurred during the presymptomatic stage. In our estimated analysis, case detection, contact tracing, and 14-day quarantine of close contacts (regardless of symptoms) was estimated to decrease the reproduction number from the counterfactual value of 2.50 to 1.53 (95% CrI, 1.50-1.57), which would not be sufficient for epidemic control, which requires a value of less than 1. In our estimated analysis, voluntary population-based interventions, if used alone, were estimated to have reduced the reproduction number to 1.30 (95% CrI, 1.03-1.58). Combined case-based and population-based interventions were estimated to reduce the reproduction number to below unity (0.85; 95% CrI, 0.78-0.89). Results were similar for additional analyses with influenza data and sensitivity analyses. Conclusions and Relevance: In this comparative effectiveness research study, the combination of case-based and population-based interventions (with wide adherence) may explain the success of COVID-19 control in Taiwan in 2020. Either category of interventions alone would have been insufficient, even in a country with an effective public health system and comprehensive contact tracing program. Mitigating the COVID-19 pandemic requires the collaborative effort of public health professionals and the general public.

Proactive and blended approach for COVID-19 control in Taiwan.

Coronavirus disease 2019 (COVID-19) has become the greatest threat to human society in a century. To better devise control strategies, policymakers should adjust policies based on scientific evidence in hand. Several countries have limited the epidemics of COVID-19 by prioritizing containment strategies to mitigate the impacts on public health and healthcare systems. However, asymptomatic/pre-symptomatic transmission of COVID-19 complicated traditional symptom-based approaches for disease control. In addition, drastic population-based interventions usually have significant societal and economic impacts. Therefore, in Taiwan, the containment strategies consisted of the more extended case-based interventions (e.g., case detection with enhanced surveillance and contact tracing with active monitoring and quarantine of close contacts) and more targeted population-based interventions (e.g., face mask use in recommended settings and risk-oriented border control with corresponding quarantine requirement). The success of the blended approach emphasizes not only the importance of evidence-supported policymaking but also the coordinated efforts between the government and the people.

Contact tracing with digital assistance in Taiwan's COVID-19 outbreak response.

AIM: Comprehensive case investigation and contact tracing are crucial to prevent community spread of COVID-19. We demonstrated a utility of using traditional contact tracing measures supplemented with symptom tracking and contact management system to assist public health workers with high efficiency. METHODS: A centralized contact tracing system was developed to support data linkage, cross-jurisdictional coordination, and follow-up of contacts' health status. We illustrated the process of how digital tools support contact tracing and management of COVID-19 cases and measured the timeliness from case detection to contact monitoring to evaluate system performance. RESULTS: Among the 8051 close contacts of the 487 confirmed cases (16.5 close contacts/case, 95% CI [13.9-19.1]), the median elapsed time from last exposure to quarantine was three days (IQR 1-5). By implementing the approach of self-reporting using automatic text-messages and web-app, the percentage of health status updates from self-reporting increased from 22.5% to 61.5%. The high proportion of secondary cases detected via contact tracing (88%) might reduce the R0 to under one and minimize the impact of local transmission in the community. CONCLUSION: Comprehensive contact tracing and management with complementary technology would still be a pillar of strategies for containing outbreaks during de-escalation or early in the next wave of COVID-19 pandemic.

Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset.

Importance: The dynamics of coronavirus disease 2019 (COVID-19) transmissibility are yet to be fully understood. Better understanding of the transmission dynamics is important for the development and evaluation of effective control policies. Objective: To delineate the transmission dynamics of COVID-19 and evaluate the transmission risk at different exposure window periods before and after symptom onset. Design, Setting, and Participants: This prospective case-ascertained study in Taiwan included laboratory-confirmed cases of COVID-19 and their contacts. The study period was from January 15 to March 18, 2020. All close contacts were quarantined at home for 14 days after their last exposure to the index case. During the quarantine period, any relevant symptoms (fever, cough, or other respiratory symptoms) of contacts triggered a COVID-19 test. The final follow-up date was April 2, 2020. Main Outcomes and Measures: Secondary clinical attack rate (considering symptomatic cases only) for different exposure time windows of the index cases and for different exposure settings (such as household, family, and health care). Results: We enrolled 100 confirmed patients, with a median age of 44 years (range, 11-88 years), including 44 men and 56 women. Among their 2761 close contacts, there were 22 paired index-secondary cases. The overall secondary clinical attack rate was 0.7% (95% CI, 0.4%-1.0%). The attack rate was higher among the 1818 contacts whose exposure to index cases started within 5 days of symptom onset (1.0% [95% CI, 0.6%-1.6%]) compared with those who were exposed later (0 cases from 852 contacts; 95% CI, 0%-0.4%). The 299 contacts with exclusive presymptomatic exposures were also at risk (attack rate, 0.7% [95% CI, 0.2%-2.4%]). The attack rate was higher among household (4.6% [95% CI, 2.3%-9.3%]) and nonhousehold (5.3% [95% CI, 2.1%-12.8%]) family contacts than that in health care or other settings. The attack rates were higher among those aged 40 to 59 years (1.1% [95% CI, 0.6%-2.1%]) and those aged 60 years and older (0.9% [95% CI, 0.3%-2.6%]). Conclusions and Relevance: In this study, high transmissibility of COVID-19 before and immediately after symptom onset suggests that finding and isolating symptomatic patients alone may not suffice to contain the epidemic, and more generalized measures may be required, such as social distancing.