Emerging Infectious Diseases

Zika

The Zika virus (ZIKV) is a mosquito-borne flavivirus related to dengue, yellow fever, Japanese encephalitis and West Nile viruses. ZIKV is primarily transmitted by Aedes mosquitoes, which can also transmit Chikungunya, dengue, yellow fever and West Nile viruses. Human-to-human transmission of ZIKV occurs through sexual contact, blood transfusion, as well as from mother to foetus during pregnancy. ZIKV infection is usually asymptomatic, with mild symptoms including fever, muscle and joint pain, rash, conjunctivitis, and headache.

Severe complications arise due to ZIKV-inducing Guillain-Barré syndrome (GBS) – an autoimmune condition – in adults, or upon infection during pregnancy, resulting in congenital Zika syndromes (CZS), which include microcephaly, central nervous system malformations and a host of other neurological abnormalities in infants. Between 5% and 15% of infants born to ZIKV-infected women may present with CZS.

Aedes mosquitoes are widespread, with local transmission of ZIKV reported in Africa, South-East Asia, the Pacific region, the Americas and Europe. Although ZIKV was first reported in Uganda in 1947 and spread to Asia in the 1960s, the first significant outbreak was reported in Micronesia in 2007 (49 confirmed GBS cases and no deaths). In 2013, another outbreak began in French Polynesia, spreading to other Pacific Islands, with 30,000 suspected cases (coinciding with a spike in cases of GBS). In 2015, the largest ever Zika outbreak occurred in Brazil, and soon spread elsewhere in the Americas and beyond. At the end of this outbreak in late 2016, there were 128,793 confirmed cases of ZIKV infections reported, with 2,289 newborns confirmed with CZS.

R&D needs

Research is ongoing for potential therapies and vaccines to prevent Zika virus infection and Congenital Zika Syndromes (CZS). However, further investigation of epidemiology, clinical manifestations, and long-term sequelae of CZS is urgently needed.

The ideal prospective vaccine should be appropriate for both endemic and outbreak settings and have an excellent safety profile in pregnant and lactating women. The most advanced candidate is a DNA vaccine (VRC 705), which completed Phase II trials in October 2019.  Multiple additional vaccine candidates are currently in Phase I trials. While the Zika vaccine pipeline has progressed significantly, the low incidence and unpredictable nature of the outbreaks, diversity of clinical manifestations and infeasibility of trials using CZS as the primary endpoint make it difficult to conduct late-stage efficacy trials. Alternative approaches, such as accelerated regulatory pathways with immune correlates or animal rule, Controlled Human Infection Models or surrogates as endpoints are under consideration.

Ideal treatments for Zika should be suitable for both therapeutic use for treating intra-uterine infection and prophylactic use, including prevention of mother to child infections. Even with the licensure of a Zika vaccine, drugs can play a valuable preventive role in areas of low endemicity. Currently, two biologics – a human monoclonal antibody (Tyzivumab) and an immunoglobulin (ZIKV-IG/NP-024) – are the only therapeutics in clinical development. The single biggest challenge in developing Zika therapeutics is the discovery of an agent which is not teratogenic but which can prevent congenital Zika infection.

The diagnostic pipeline for Zika has improved since 2015, with multiple point-of-care (POC) or near-POC molecular and serological assays already approved by the US FDA and WHO under both emergency use and standard pathways. However, none of the FDA approved PoC tests adequately addresses multiplexing with other co-endemic and cross-reacting flaviviruses, such as dengue and Chikungunya.

Aedes mosquito control programmes in Zika-affected countries must overcome urban outdoor transmission and high levels of infestation. Several recent field studies have confirmed reduced incidence of arboviral diseases after implementation of Wolbachia-based microbial control, while as-yet-unvalidated modelling studies suggest high efficacy of genetic manipulation.

Pipeline spotlight

Two repurposed drugs, Asunaprevir and Simeprevir, have exhibited potent antiviral activities in in vitro studies while another broad-spectrum antiviral, Galidesivir, is undergoing preclinical evaluation in macaque apes. Biologics Tyzivumab and ZIKV-IG/NP-024 have successfully completed Phase I trials and are under further clinical development. In 2021, an RNA vaccine, mRNA-1893, entered Phase II trials.