Estimates of reduced vaccine effectiveness against hospitalization, infection, transmission and symptomatic disease of a new SARS-CoV-2 variant, Omicron (B.1.1.529), using neutralizing antibody titers (preprint)

The emergence of the Omicron variant (B.1.1.529) of SARS-CoV-2 has raised concerns about how mutations in the spike protein might influence immune escape and vaccine protection against infection and disease, COVID-19. Initial estimates of immune escape measure neutralizing antibody titers, which have been shown to be a correlate of protection for COVID-19, but vary among studies. However, no studies have examined variation in vaccine effectiveness (VE) using estimated reductions in neutralizing antibody titers across virus variants. We quantified consistency in relative neutralizing antibody titers across studies. We then examined relationships between variant-specific reductions in neutralizing antibodies and protection against documented infection, symptomatic disease, and hospitalizations across variants and vaccines. We found considerable variation in variant-specific neutralizing antibody titers between studies, but within-study comparisons across variants were far more robust. There was insufficient data to estimate VE for a single vaccine across variants, especially for higher levels of immune evasion (>7-fold reductions in neutralizing antibody titers) observed with the Omicron variant (40-fold). Instead, we leveraged variation among both vaccines and virus variants to estimate VE -neutralizing antibody titer relationships across a 30 to 100-fold range of neutralizing antibody titers reduction. Omicron increased the risk of hospitalization four to five-fold and increased the risk of symptomatic disease seven to ten-fold for mRNA vaccinees, with similar relative effects for recently vaccinated, or individuals with waned antibody titers. Third doses restored titers and protection to levels similar to waned immunity against Delta. Overall, these analyses indicate that vaccine effectiveness against severe disease is significantly diminished for waned individuals, and protection against infection, symptomatic disease and transmission is nearly eliminated. However, third doses significantly ameliorate these reductions but only restore protection to levels equivalent to waned protection against the Delta variant. The invasion of Omicron is likely to result in widespread infection, and substantial hospitalizations unless widespread boosting of immunity occurs. Funding California Department of Health, National Science Foundation

Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations (preprint)

BackgroundVaccines have greatly reduced the impact of COVID-19, but vaccine protection against milder disease and infection have waned significantly, especially for the Delta variant (B.1.617.2). A third booster dose of two-dose vaccines could restore protection but the benefit of boosting immunity in younger healthy individuals and the resultant effects on transmission have not been quantified. MethodsWe develop relationships between neutralizing antibody titers and vaccine protection against both infection and transmission. We combine these relationships with data on waning and boosting of neutralizing antibody titers to examine the impact of third doses of Pfizer-BioNtech and Moderna vaccines on infection and transmission and the impact on the pathogen effective reproductive number Rt. FindingsWaning reduced protection of the Pfizer-BioNtech vaccine against all infections from 80.0% (95% CI: 77% to 83%) to 60.4% (95% CI: 53% to 67%), and for the Moderna vaccine from 83.8 (95% CI: 80 to 87%) to 65.9% (95% CI: 61-71%). A third dose increased neutralizing antibody titers 25.9-fold relative to waned levels for the Pfizer-BioNtech vaccine and 13-fold relative to waned levels for the Moderna vaccine. This increased protection against infection to 87.2% (95% CI: 83% to 91%) and 86.3% (95% CI: 82% to 90%) for Pfizer and Moderna, respectively. Increased protection against infection and transmission from third doses reduced Rt by 28% to 74% depending on vaccine coverage and previous infection and reduced Rt below 1 when vaccination coverage was high or contact rates were well below pre-pandemic levels. InterpretationA third vaccine dose could substantially reduce transmission of SARS-CoV-2 and prevent future surges, with the impact increasing with vaccine coverage and contact rates among individuals. Reducing transmission would reduce infection in both unvaccinated individuals and breakthrough infections in vaccinated individuals. FundingCalifornia Department of Health, National Science Foundation

Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts (preprint)

Quarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.

A new SARS-CoV-2 lineage that shares mutations with known Variants of Concern is rejected by automated sequence repository quality control (preprint)

We report a SARS-CoV-2 lineage that shares N501Y, P681H, and other mutations with known variants of concern, such as B.1.1.7. This lineage, which we refer to as B.1.x (COG-UK sometimes references similar samples as B.1.324.1), is present in at least 20 states across the USA and in at least six countries. However, a large deletion causes the sequence to be automatically rejected from repositories, suggesting that the frequency of this new lineage is underestimated using public data. Recent dynamics based on 339 samples obtained in Santa Cruz County, CA, USA suggest that B.1.x may be increasing in frequency at a rate similar to that of B.1.1.7 in Southern California. At present the functional differences between this variant B.1.x and other circulating SARS-CoV-2 variants are unknown, and further studies on secondary attack rates, viral loads, immune evasion and/or disease severity are needed to determine if it poses a public health concern. Nonetheless, given what is known from well-studied circulating variants of concern, it seems unlikely that the lineage could pose larger concerns for human health than many already globally distributed lineages. Our work highlights a need for rapid turnaround time from sequence generation to submission and improved sequence quality control that removes submission bias. We identify promising paths toward this goal.

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.

Age-Stratified SARS-CoV-2 Infection Fatality Rates in New York City estimated from serological data (preprint)

Importance: COVID-19 has killed hundreds of thousands of people in the US and >1 million globally. Estimating the age-specific infection fatality rate (IFR) of SARS-CoV-2 for different populations is crucial for assessing the fatality of COVID-19 and for appropriately allocating limited vaccine supplies to minimize mortality. Objective: To estimate IFRs for COVID-19 in New York City and compare them to IFRs from other countries. Design, Setting, Participants: We used data from a published serosurvey of 5946 individuals 18 years or older conducted April 19-28, 2020 with time series of COVID-19 confirmed cases and deaths for five age-classes from the New York City Department of Health and Mental Hygiene. We inferred age-specific IFRs using a Bayesian framework that accounted for the distribution of delay between infection and seroconversion and infection and death. Main Outcome and Measure: Infection fatality rate. Results: We found that IFRs increased approximately 77-fold with age, with a nearly linear increase on a log scale, from 0.07% (0.055%-0.086%) in 18-44 year olds to 5.4% (4.3%-6.3%) in individuals 75 and older. New York City IFRs were higher for 18-44 year olds and 45-64 year olds (0.58%; 0.45%-0.75%) than Spanish, English, and Swiss populations, but IFRs for 75+ year olds were lower than for English populations and similar to Spanish and Swiss populations. Conclusions and Relevance: These results suggest that the age-specific fatality of COVID-19 differs among developed countries and raises questions about factors underlying these differences.

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.

Contact tracing efficiency, transmission heterogeneity, and accelerating COVID-19 epidemics (preprint)

Simultaneously controlling COVID-19 epidemics and limiting economic and societal impacts presents a difficult challenge, especially with limited public health budgets. Testing, contact tracing, and isolating/quarantining is a key strategy that has been used to reduce transmission of SARS-CoV-2, the virus that causes COVID-19. However, manual contact tracing is a time-consuming process and as case numbers increase it takes longer to reach each cases contacts, leading to additional virus spread. Delays between symptom onset and being tested (and receiving results), and a low fraction of symptomatic cases being tested can also reduce the impact of contact tracing on transmission. We examined the relationship between cases, delays, and participation and the pathogen reproductive number Rt. We also examined implications for infection dynamics using a stochastic compartment model of SARS-CoV-2. We found that Rt increases sigmoidally with the number of cases due to decreasing contact tracing efficacy. This relationship results in accelerating epidemics because Rt increases, rather than declines, as infections increase. Shifting contact tracers from locations with high and low case burdens relative to capacity to locations with intermediate case burdens maximizes their impact in reducing Rt (but minimizing total infections is more complicated). We also found that contact tracing quickly becomes ineffective in reducing Rt with increasing delays between symptom onset and tracing and with lower fraction of symptomatic infections being tested. Finally, we found that when cases are low, testing and tracing reductions in Rt can sometimes greatly delay epidemics due to the highly heterogeneous transmission dynamics of SARS-CoV-2, in which a small fraction of infections often give rise to most of transmission. These results demonstrate the importance of having an expandable or mobile team of contact tracers that can be used to control surges in cases. They also emphasize the value of easy access, high testing capacity and rapid turn-around of testing results, as well as outreach efforts to encourage symptomatic infections to be tested immediately after symptom onset. An efficient and adaptive public health capacity strategy can allow for increased economic activity and should be employed in the current and future pandemics.

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.