The emergence of the SARS-CoV-2 Omicron variant capable of escaping neutralizing antibodies emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Nasal epithelium is rich in the ACE2 receptor and important for SARS-CoV-2 transmission by supporting early viral replication before seeding to the lung1. Intranasal administration of SARS-CoV-2 neutralizing antibodies or antibody fragments has shown encouraging potential as a protective measure in animal models2-5. However, there remains a need for SARS-CoV-2 blocking agents that are more economical to produce in large scale, while less vulnerable to mutational variation in the neutralization epitopes of the viral Spike glycoprotein. Here we describe TriSb92, a highly manufacturable trimeric human nephrocystin SH3 domain-derived antibody mimetic targeted against a conserved region in the receptor-binding domain of the Spike. TriSb92 potently neutralizes SARS-CoV-2 and its variants of concern, including Delta and Omicron. Intranasal administration of a modest dose of TriSb92 (5 or 50 micrograms) as early as eight hours before the challenge with SARS-CoV-2 B.1.351 efficiently protected mice from infection. The target epitope of TriSb92 was defined by cryo-EM, which revealed triggering of a conformational shift in the Spike trimer rather than competition for ACE2 binding as the molecular basis of its strong inhibitory action. Our results highlight the potential of intranasal inhibitors in protecting susceptible individuals from SARS-CoV-2 infection, and describe a novel type of inhibitor that could be of use in addressing the challenge posed by the Omicron variant.
The role of contact tracing in COVID-19
Case-based interventions such as case isolation or contact tracing with quarantine have been crucial in controlling the ongoing COVID-19 pandemic, while reducing the need for indiscriminate contact reductions with high economic cost1,2.
Contact tracing aims to identify and interrupt transmission chains by isolating infected patients and quarantining those at risk from infection. More infections are prevented, and epidemic control is improved, if the identification of patients and contacts at risk is rapid and comprehensive3–6. It has been a staple public health intervention in a variety of infectious diseases, notably sexually transmitted diseases and tuberculosis7,8.
Worldwide investments in contact tracing programs and research on the topic have not prevented repeated resurgence of community transmission of COVID-19, underscoring the urgent need for improved knowledge on the effective implementation of this key public health measure6,9.
Forward contact tracing
Forward contact tracing of an index case (the person diagnosed with COVID-19 undergoing contact tracing) intends to interrupt onward transmission from child cases (persons infected by the index case) by quarantining and/or testing contacts the index case has encountered during their infectious period10–12. In the light of substantial asymptomatic and pre-symptomatic transmission, the infectious period is generally assumed to start 2 days prior to onset of symptoms or diagnosis, whichever came first13–18. In addition to child cases, any practical forward tracing strategy probably identifies the parent case (the infector of the index case) and sibling cases (infected by the same parent case) some of the time, for example if the index case had repeated contact with their parent or sibling case during their own infectious period, or if the time from the index case’s infection to their symptom onset or diagnosis was less than two days12. Forward contact tracing is the focus in most jurisdictions and has shown its ability to decrease COVID-19 transmission (Fig. 1)13,14,19.
Backward contact tracing
Backward contact tracing, or bidirectional contact tracing, which combines both approaches, specifically aims to identify the parent case and sibling cases by going back further in time5,10−12. In any practical implementation, additional child cases may also be identified through backward contact tracing, for example if the index case’s infectiousness started more than two days before symptom onset12.
Backward contact tracing is particularly promising in COVID-19 because a small proportion of index cases, the so-called superspreaders, generate the majority of secondary infections11,20−27. This phenomenon favours allocating resources to the identification of source cases and events, as a high rate of infection can be expected amongst individuals exposed to the same source. Endo et al estimate bidirectional contact tracing to result in 2–3 times the number of subsequent cases averted compared to forward contact tracing alone in a simple branching model for COVID-1910. Kojaku et al show backward contact tracing to be highly effective in terms of the number of prevented cases per quarantine when running an SEIR (Susceptible-Exposed-Infectious-Removed) model on synthetic and empirical contact networks, even if contact tracing comprehensiveness is low11.
One potential difficulty of backward contact tracing lies in the inherent delays involved in testing, tracing and quarantine – where infected contacts who are sibling or parent cases risk being detected after or near to the end of their infectious period3,18. This could reduce efficiency and increase the relative cost of testing and quarantine (Fig. 1). Due to these delays, immediate testing of identified contacts in support of iterative tracing may be especially relevant in backward contact tracing.
Types of backward contact tracing
The real-world implementation of backward contact tracing can be broadly subdivided into a source event approach and an extended contact tracing window approach (Fig. 2).
Several countries have rolled out an approach focusing on source events, which are events where the index case is suspected to have contracted COVID-19. The identification of such an event leads to the screening of attendants at risk, which usually includes more individuals than the direct contacts of the index case under investigation28–32. This is because the risk at these events is not related to the index case, but to an unknown parent case. High positivity rates have been reported for attendants of some source events33. In practice, this approach is usually reliant on the identification of multiple confirmed or probable infected cases at the same event, for example by pooling of contact tracing data from different index cases or asking the index case about other cases in their environment. As a result, the approach can fail to identify the source event at the time of identification of the initial index case.
Another approach is to extend the contact tracing window back in time and to systematically refer all close contacts for quarantine and/or testing (Fig. 1, 2). This assumes that, if the tracing window is extended backward by at least the incubation period of the index case, the parent case can be identified, as well as sibling cases present at a shared source event. To this end, the contact tracing window should be extended far enough to include most of the variability in incubation periods34.
Several modelling studies underscore the benefits of extending the contact tracing window for COVID-19. Bradshaw et al show in a stochastic branching-process model that extending the contact tracing window from 2 to 6 days before onset or diagnoses improves the reduction in the effective reproduction number by 85%-275% when using manual contact tracing only (performed by humans rather than through digital means)12. Their findings are robust to contextual factors such as case ascertainment rate, test sensitivity, basic reproduction number and the percentages of asymptomatic, pre-symptomatic and environmental transmission. Fyles et al also show in a branching process model that an extended contact tracing window results in a linear decrease in the growth rate up until around 8 to 10 days prior to symptom onset or diagnosis, although additional gains are highly reliant on recall decay5.
Hypothesis and research question
Whilst there is evidence from modelling studies pointing at the potential benefits of backward contact tracing, no study has evaluated the efficiency in practice. The positivity rate of screened contacts has been proposed as an indicator for efficient allocation of testing and quarantine35,36. In this cohort study we thus determined the positivity rate of additional close contacts (for the purpose of this article this includes co-attendants of high risk events of up to 20 persons) identified in an extended contact tracing window, starting 7 days before onset of symptoms or diagnosis, whichever was earlier. This window was chosen to include the source event most of the time 32–34. We tested the hypothesis that the positivity rate amongst additional contacts in the extended tracing window would be at least as high as amongst a control group of patients attending the test centre for symptoms suggestive of COVID-19. In a first subgroup analysis, we explored how far back the contact tracing window should extend, by calculating the positivity rate of identified contacts grouped by day of last exposure. Our second hypothesis was that the risk would not be limited to possible source events identified at the time of the tracing interview. Therefore, the second subgroup analysis compared our strategy to a source investigation approach, by subgrouping contacts last exposed in the extended contact tracing window according to presence at suspected source events.
