Incubation-period estimates of Omicron (BA.1) variant from Taiwan, December 2021-January 2022, and its comparison to other SARS-CoV-2 variants: a statistical modeling, systematic search and meta-analysis (preprint)

Background: The ongoing COVID-19 pandemic has seen several variants of concern, including the Omicron (BA.1) variant which emerged in October 2021. Accurately estimating the incubation period of these variants is crucial for predicting disease spread and formulating effective public health strategies. However, existing estimates often conflict because of biases arising from the dynamic nature of epidemic growth and selective inclusion of cases. This study aims to accurately estimate of the Omicron (BA.1) variant incubation period based on data from Taiwan, where disease incidence remained low and contact tracing was comprehensive during the first months of the Omicron outbreak. Methods: We reviewed 100 contact-tracing records for cases of the Omicron BA.1 variant reported between December 2021 and January 2022, and found enough information to analyze 70 of these. The incubation period distribution was estimated by fitting data on exposure and symptom onset within a Bayesian mixture model using gamma, Weibull, and lognormal distributions as candidates. Additionally, a systematic literature search was conducted to accumulate data for estimates of the incubation period for Omicron (BA.1/2, BA.4/5) subvariants, which was then used for meta-analysis and comparison. Results: The mean incubation period was estimated at 3.5 days (95% credible interval: 3.1-4.0 days), with no clear differences when stratified by vaccination status or age. This estimate aligns closely with the pooled mean of 3.4 days (3.0-3.8 days) obtained from a meta-analysis of other published studies on Omicron subvariants. Conclusions: The relatively shorter incubation period of the Omicron variant, as compared to previous SARS-CoV2 variants, implies its potential for rapid spread but also opens the possibility for individuals to voluntarily adopt shorter, more resource-efficient quarantine periods. Continual updates to incubation period estimates, utilizing data from comprehensive contact tracing, are crucial for effectively guiding these voluntary actions and adjusting high socio-economic cost interventions.

Safety and immunogenicity of SARS-CoV-2 vaccine MVC-COV1901 in Taiwanese adolescents: A double-blind, randomized, placebo-controlled phase 2 trial (preprint)

Adolescents and children play 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 been approved for use in adults in Taiwan. In this study, we have investigated the safety and immunogenicity of two doses of MVC-COV1901 in adolescents. Healthy adolescents from age of 12 to 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.

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 study (preprint)

Background: Data from previous studies of the MVC-COV1901 vaccine, a subunit vaccine against severe acute respiratory syndrome coronavirus 2 (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 adult and adolescents. By comparing with the active control, 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 to 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, Day 1, and 14 days after the second dose (Day 43 after first dose). Primary and secondary safety and immunogenicity endpoints were assessed. In addition, other outcomes investigated were cross-reactive immunity against the Omicron strain and non-neutralizing antibody immune effector mechanisms particularly 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. The mean age was 32.1 years and approximately 60% were males. An estimated 35.3% of participants had coexisiting medical conditions. When compared against AZD1222, MVC-COV1901 exhibited superiority in terms of neutralizing antibody titers geometric mean titer ratio (GMTR) [GMTR seronegative: 4.8 (95% CI 3.0-7.7); GMTR seropositive: 1.7 (95% CI 1.2-2.2)] and non-inferiority in terms of seroconversion rates. Reactogenicity was generally mild. The incidence of serious adverse events was low in both groups. Both vaccines have a Th1-biased response that is predominated by the production of IgG1 and IgG3 subclasses-with MVC-COV1901 exhibiting a stronger antibody response. In the pseudovirus assay, Omicron-neutralizing titers were 44.5 times lower compared to wildtype-neutralizing titers among seronegative individuals at baseline. This fold-reduction was reduced to 3.0 times among the seropositive. Conclusion: Safety and immunogenicity data presented here demonstrate the safe and robust immunogenicity from MVC-COV1901. 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 adolescents in Taiwan: A double-blind, randomized, placebo-controlled phase 2 trial (preprint)

Background: MVC-COV1901 is a subunit SARS-CoV-2 vaccine based on the prefusion spike protein S-2P and adjuvanted with CpG 1018 and aluminum hydroxide. Although MVC-COV1901 has been licensed for emergency use for adults in Taiwan, the safety and immunogenicity of MVC-COV1901 in adolescents remained unknown. As young people play an important role in SARS-CoV-2 transmission and epidemiology, a vaccine approved for adolescents and eventually, children, will be important in mitigating the COVID-19 pandemic. Methods: This study is a prospective, double-blind, multi-center phase 2 trial evaluating the safety, tolerability and immunogenicity of two doses of the SARS-CoV-2 vaccine MVC-COV1901 in adolescents. Healthy adolescents from age of 12 to 17 years were recruited and randomly assigned (6:1) to receive two intramuscular doses of either MVC-COV1901 or placebo at 28 days apart. The primary outcomes were safety and immunogenicity from the day of first vaccination (Day 1) to 28 days after the second vaccination (Day 57), and immunogenicity of MVC COV1901 in adolescents as compared to young adult vaccinees in terms of neutralizing antibody titers and seroconversion rate. The secondary outcomes were safety and immunogenicity of MVC-COV1901 as compared to placebo in adolescents in terms of immunoglobulin titers and neutralizing antibody titers over the study period. Results: Between July 21, 2021 and December 22, 2021, a total of 399 adolescent participants were included for safety evaluation after enrollment to receive at least one dose of either MVC-COV1901 (N=341) or placebo (N=58). Of these, 334 and 46 participants went on to receive two doses of either MVC-COV1901 or placebo, respectively, and were included in the per protocol set (PPS) for immunogenicity analysis. Adverse events were mostly mild and were similar in MVC-COV1901 and placebo groups. The most commonly reported adverse events were 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. Conclusions: The safety and immunogenicity data presented here showed that MVC-COV1901 has similar safety profile and non-inferior immunogenicity in adolescents compared to young adults.

The reactogenicity and immunogenicity of a booster dose after the second dose of a protein subunit vaccine MVC-COV1901. (preprint)

Abstract: In this extension of the phase 1 clinical study, we report the immunogenicity and reactogenicity of the booster dose of a COVID-19 vaccine, MVC-COV1901, administered six months after the completion of the primary two dose schedule. Antibody persistence was detected at 6 months after the second dose of MVC-COV1901, albeit at reduced levels. At 28 days after the booster dose, the neutralizing antibody titer was 1.7-fold higher compared to the previous peak at 2 weeks after the second dose. These data demonstrated the safety and immunogenicity of booster shot of MVC-COV1901 after the primary schedule of the vaccine.

The Timing of COVID-19 Transmission (preprint)

Background: The timing of SARS-CoV-2 transmission is a critical factor to understand the epidemic trajectory and the impact of isolation, contact tracing and other non-pharmaceutical interventions on the spread of COVID-19 epidemics. Methods: We examined the distribution of transmission event times with respect to exposure and onset of symptoms. We analysed 119 transmission pairs with known date of onset of symptoms for both index and secondary cases and partial information on their intervals of exposure. We inferred the distribution for generation time and time from onset of symptoms to transmission by maximum likelihood. We modelled different relations between time of infection, onset of symptoms and transmission, inferring the most appropriate one according to the Akaike Information Criterion. Finally, we estimated the fraction of pre-symptomatic and early symptomatic transmissions among all pairs using a Bayesian approach.Findings: For symptomatic individuals, the timing of transmission of SARS-CoV-2 was more directly linked to the onset of clinical symptoms of COVID-19 than to the time since infection. The time of transmission was approximately centered and symmetric around the onset of symptoms, with three quarters of events occurring in the window from 2-3 days before to 2-3 days after. The pre-symptomatic infectious period extended further back in time for individuals with longer incubation periods. Overall, the fraction of transmission from strictly pre-symptomatic infections was high (41%; 95%CI 31-50%), but a comparably large fraction of transmissions occurred on the same day as the onset of symptoms or the next day (35%; 95%CI 26-45%). We caution against overinterpretation of the fraction and timing of late symptomatic transmissions, due to their dependence on behavioural factors and interventions. Interpretation: Infectiousness is causally driven by the onset of symptoms. Public health authorities should reassess their policies on the contact tracing window in the light of individual variability in presymptomatic infectious period. Information about when a case was infected should be collected where possible, in order to assess how far into the past their contacts should be traced. The large fraction of transmission from strictly pre-symptomatic infections limits the efficacy of symptom-based interventions, while the large fraction of early symptomatic transmissions underlines the critical importance of individuals distancing themselves from others as soon as they notice any symptoms, even if mild. Rapid or at-home testing and contextual risk information could greatly facilitate efficient early isolation.Funding Statement: The study was funded by an award from the Li Ka Shing Foundation to CF.Declaration of Interests: None of the authors have competing financial or non-financial interests.

The timing of COVID-19 transmission (preprint)

The timing of SARS-CoV-2 transmission is a critical factor to understand the epidemic trajectory and the impact of isolation, contact tracing and other non- pharmaceutical interventions on the spread of COVID-19 epidemics. We examined the distribution of transmission events with respect to exposure and onset of symptoms. We show that for symptomatic individuals, the timing of transmission of SARS-CoV-2 is more strongly linked to the onset of clinical symptoms of COVID-19 than to the time since infection. We found that it was approximately centered and symmetric around the onset of symptoms, with three quarters of events occurring in the window from 2-3 days before to 2-3 days after. However, we caution against overinterpretation of the right tail of the distribution, due to its dependence on behavioural factors and interventions. We also found that the pre-symptomatic infectious period extended further back in time for individuals with longer incubation periods. This strongly suggests that information about when a case was infected should be collected where possible, in order to assess how far into the past their contacts should be traced. Overall, the fraction of transmission from strictly pre-symptomatic infections was high (41%; 95%CI 31-50%), which limits the efficacy of symptom-based interventions, and the large fraction of transmissions (35%; 95%CI 26-45%) that occur on the same day or the day after onset of symptoms underlines the critical importance of individuals distancing themselves from others as soon as they notice any symptoms, even if they are mild. Rapid or at-home testing and contextual risk information would greatly facilitate efficient early isolation.

Mutational Analysis of SARS-CoV-2 Genome in African Population (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly infectious and pathogenic virus has claimed lot of lives globally since its outbreak in December 2019 posing dire threat on public health, global economy, social and human interaction. At moderate rate, mutations in the SARS-CoV-2 genome are evolving which might have contributed to viral genome variability, transmission, replication efficiency and virulence in different regions of the world. The present study elucidated the mutational landscape in SARS-CoV-2 genome among the African population, which may have contributed to the virulence, pathogenicity and transmission observed in the region. Multiple sequence alignment of the SARS-CoV-2 genome (356 viral protein sequences) was performed using ClustalX version 2.1 and phylogenetic tree was built using Molecular Evolutionary Genetics Analysis (MEGA) X software. ORF1ab polyprotein, spike glycoprotein, ORF3, ORF8 and nucleocapsid phosphoprotein were observed as mutational hotspots in the African population and may be of keen interest in the adaptability of SARS-CoV-2 to the human host. While, there is conservation in the envelope protein, membrane glycoprotein, ORF6, ORF7a, ORF7b and ORF10. The accumulation of moderate mutations (though slowly) in the SARS-CoV-2 genome as revealed in our study, could be a promising strategy to develop drugs or vaccines with respect to the viral conserved domains and host cellular proteins and/or receptors involved in viral invasion and replication to avoid a new viral wave due to drug resistance and vaccine evasion.

The SARS-CoV-2 multibasic cleavage site facilitates early serine protease-mediated entry into organoid-derived human airway cells (preprint)

After the SARS-CoV outbreak in 2003, a second zoonotic coronavirus named SARS-CoV-2, emerged late 2019 in China and rapidly caused the COVID-19 pandemic leading to a public health crisis of an unprecedented scale. Despite the fact that SARS-CoV-2 uses the same receptor as SARS-CoV, transmission and pathogenesis of both viruses seem to be quite distinct. A remarkable feature of the SARS-CoV-2 spike is the presence of a multibasic cleavage site, which is absent in the SARS-CoV spike. The viral spike protein not only attaches to the entry receptor, but also mediates fusion after cleavage by host proteases. Here, we report that the SARS-CoV-2 spike multibasic cleavage site increases infectivity on differentiated organoid-derived human airway cells. Compared with SARS-CoV, SARS-CoV-2 entered faster into the lung cell line Calu-3, and more frequently formed syncytial cells in differentiated organoid-derived human airway cells. Moreover, the multibasic cleavage site increased entry speed and plasma membrane serine protease usage relative to endosomal entry using cathepsins. Blocking serine protease activity using the clinically approved drug camostat mesylate effectively inhibited SARS-CoV-2 entry and replication in differentiated organoid-derived human airway cells. Our findings provide novel information on how SARS-CoV-2 enters relevant airway cells and highlight serine proteases as an attractive antiviral target.

Effects of case- and population-based COVID-19 interventions in Taiwan (preprint)

In the first wave of the COVID-19 pandemic, broad usage of non-pharmaceutical interventions played a crucial role in controlling epidemics. However, the substantial economic and societal costs of continuous use of border controls, travel restrictions, and physical distancing measures suggest that these measures may not be sustainable and that policymakers have to seek strategies to lift the restrictions. Taiwan was one of the few countries that demonstrated initial success in eliminating the COVID-19 outbreak without strict lockdown or school closure. To understand the key contributors to the successful control, we applied a stochastic branching model to empirical case data to evaluate and compare the effectiveness of more targeted case-based (including contact tracing and quarantine) and less targeted population-based interventions (including social distancing and face mask use) in Taiwan. We found that case-based interventions alone would not be sufficient to contain the epidemic, even in a setting where a highly efficient contact tracing program was in place. The voluntary population-based interventions have reduced the reproduction numbers by more than 60% and have likely played a critical role at the early stage of the outbreak. Our analysis of Taiwan's success highlights that coordinated efforts from both the government and the citizens are indispensable in the fight against COVID-19 pandemic.

High transmissibility of COVID-19 near symptom onset (preprint)

Background The dynamics of coronavirus disease 2019 (COVID-19) transmissibility after symptom onset remains unknown. Methods We conducted a prospective case-ascertained study on laboratory-confirmed COVID-19 cases and their contacts. Secondary clinical attack rate (considering symptomatic cases only) was analyzed for different exposure windows after symptom onset of index cases and for different exposure settings. Results Thirty-two confirmed patients were enrolled and 12 paired data (index-secondary cases) were identified among the 1,043 contacts. The secondary clinical attack rate was 0.9% (95% CI 0.5-1.7%). The attack rate was higher among those whose exposure to index cases started within five days of symptom onset (2.4%, 95% CI 1.1-4.5%) than those who were exposed later (zero case from 605 close contacts, 95% CI 0-0.61%). The attack rate was also higher among household contacts (13.6%, 95% CI 4.7-29.5%) and non-household family contacts (8.5%, 95% CI 2.4-20.3%) than that in healthcare or other settings. The higher secondary clinical attack rate for contacts near symptom onset remained when the analysis was restricted to household and family contacts. There was a trend of increasing attack rate with the age of contacts (p for trend < 0.001). Conclusions High transmissibility of COVID-19 near symptom onset suggests that finding and isolating symptomatic patients alone may not suffice to contain the epidemic, and more generalized social distancing measures are required. Rapid reduction of transmissibility over time implies that prolonged hospitalization of mild cases might not be necessary in large epidemics.