A deadly combination of two mosquito-borne viruses may be a trigger for stroke, new research published in the The Lancet Neurology has found.
University of Liverpool researchers and Brazilian collaborators have been investigating the link between neurological disease and infection with the viruses Zika and chikungunya.
These viruses, which mostly circulate in the tropics, cause large outbreaks of rash and fever in places like Brazil and India. Zika is widely known to cause brain damage in babies following infection in pregnancy, but the new research shows it can also cause nervous system disease in adults.
The study of 201 adults with new onset neurological disease, treated in Brazil during the 2015 Zika and 2016 chikungunya epidemics, is the largest of its kind to describe the neurological features of infection for several arboviruses circulating at the same time.
The new research shows that each virus can cause a range of neurological problems. Zika was especially likely to cause Guillain-Barre syndrome, in which the nerves in the arms and legs are damaged.
Chikungunya was more likely to cause inflammation and swelling in the brain (encephalitis) and spinal cord (myelitis). However, stroke, which could be caused by either virus alone, was more likely to occur in patients infected with the two viruses together.
Stroke occurs when one of the arteries supplying blood to the brain becomes blocked. The risk of stroke is known to be increased after some types of viral infection, like varicella zoster virus, which causes chickenpox and shingles, and HIV.
Stroke is also being recognized increasingly as a complication of COVID-19.
This has important implications for the investigation and management of patients with viral infection, as well as for understanding the mechanisms of disease.
In total 1410 patients were screened and 201 recruited over a two-year period at Hospital da Restauração in Recife, Brazil. Comprehensive PCR and antibody testing for viruses was carried out in Fiocruz laboratories.
Of the 201 patients admitted with suspected neurological disease linked to Zika, chikungunya or both, 148 had confirmation of infection on laboratory testing, around a third of whom had infection with more than one virus.
The median age of patients was 48, and just over half the patients were female. Only around 10% patients had fully recovered at discharge, with many having ongoing issues like weakness, seizures, and problems in brain function.
Of the stroke patients, who were aged 67 on average, around two thirds had infection with more than one virus. Many of the people who had a stroke had other stroke risk factors, such as high blood pressure, indicating that stroke following Zika and chikungunya viral infection may most often be seen in those who are already high risk.
Dr. Maria Lúcia Brito Ferreira, neurologist and head of department at Hospital da Restauração, leading the Brazilian team said: “Zika infection most often causes a syndrome of rash and fever without many long-term consequences, but these neurological complications – although rare – can require intensive care support in hospital, often result in disability, and may cause death.”
Dr. Suzannah Lant, a Clinical Research Fellow at the University of Liverpool, who worked on the study explained: “Our study highlights the potential effects of viral infection on the brain, with complications like stroke.
This is relevant to Zika and chikungunya, but also to our understanding of other viruses, such as COVID-19, which is increasingly being linked to neurological complications.”
Senior author Professor Tom Solomon, Director of the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool said: “Although the world’s attention is currently focused on COVID-19, other viruses that recently emerged, such as Zika and chikungunya, are continuing to circulate and cause problems. We need to understand more about why some viruses trigger stroke, so that we can try and prevent this happening in the future.”
Mosquitoes act as vectors of a remarkable number of viruses and some parasites, which they transmit in their saliva while they feed on blood. Among these mosquito-borne agents are pathogens that cause some of the most medically devastating infectious diseases – malaria, lymphatic filariasis, dengue, yellow fever, Zika virus disease, chikungunya, Japanese encephalitis, and West Nile fever.
Although some of these diseases have been around for centuries, in the past few decades epidemics caused by viruses such as West Nile, chikungunya, and Zika took many regions by surprise, overwhelming health systems.
COVID-19 has reminded the world how quickly a virus can cause havoc. The susceptibility of humans is compounded by a lack of available treatments.
Increased handwashing, controlled coughing and sneezing, and physical distancing when appropriate will reduce the future incidence of directly transmitted viruses like coronaviruses, influenza viruses, and noroviruses.
By contrast, vector-borne pathogens are unaffected by improved personal hygiene practices because their indirect transmission relies on infected arthropods (eg, mosquitoes, sandflies, ticks) or aquatic snails.
According to WHO, vector-borne pathogens account for at least 17% of all infectious diseases and each year they cause more than 700 000 deaths.
Dependency on a vector could be the weakness of vector-borne pathogens, which is the view of Jessica Manning and colleagues,1 who report in The Lancet their study of the safety and immunogenicity of a mosquito saliva peptide-based vaccine. Although blood-feeding vectors are known to induce an immune response when they feed, attempts to harness this knowledge have resulted in only two marketed vaccines, both for control of the cattle tick, but derived from midgut rather than salivary antigens.2
One reason development of an antivector vaccine has been so challenging is the evolutionary tensions between vector and vertebrate host: responses of the host (nociceptive, inflammatory, and immune) to prevent the bloodletting are countered by bioactive molecules (mostly proteins and peptides) synthesised in vector salivary glands and secreted into the host as the vector attaches and feeds.3, 4
For Manning and colleagues’ clinical trial, a vaccine was prepared comprising four peptides of 32–44 amino acids in length. The peptide sequences are predicted T-cell epitopes of proteins from Anopheles gambiae salivary glands, conserved across Anopheles, Aedes, and Culex spp mosquitoes. 49 healthy participants (30 [61%] women; median age 30·5 years [IQR 24·5–35·0]) were recruited and randomly assigned to the vaccine with adjuvant (n=17) or without adjuvant (n=16) or placebo (n=16).
Inoculation of this peptide vaccine (with or without adjuvant) had no untoward systemic effects in the 33 participants given at least one dose of vaccine, even when ten starved Aedes aegypti mosquitoes fed on them.
This basic result is encouraging given the potential for severe allergic responses. The mosquito feeding challenge could be argued to be soft – ie, Anopheles-induced immunity challenged with Aedes saliva antigens.
The outcome could have been different with A gambiae mosquitoes, although the vaccine was based on conserved antigens.
Although more safety testing needs to be done, the next big challenge is showing a mosquito peptide vaccine provides protection against mosquito-borne pathogens, which is unlikely, but not implausible. Extensive research on developing antisandfly vector vaccines to control leishmaniasis provides some design clues.5, 6
Leishmania parasites, inoculated into the skin when an infected sandfly bites, infect macrophages and form skin lesions (cutaneous forms) or migrate to the spleen, liver, and bone marrow (visceral forms).
Preclinical studies showed that rhesus macaques immunised with a sandfly salivary protein (PdSP15) were protected against cutaneous leishmaniasis when exposed to sandflies infected with the parasite.7 Protection correlated with accelerated Leishmania-specific CD4+IFN-γ+ lymphocyte production.
A similar effect was observed when mice immunised against a tick salivary protein survived an otherwise lethal challenge with ticks infected with tick-borne encephalitis virus.8
Immune responses to the vector create an environment in the skin that is hostile to pathogens that are injected during feeding, promoting a protective antipathogen response.6
The great attraction of antivector vaccines is the prospect of one vaccine protecting against all the different pathogens, known and unknown, transmitted by one vector (or even related vectors).
This approach compares favourably with conventional antipathogen approaches – eg, yellow fever vaccine protects against yellow fever virus transmitted by A aegypti but not against chikungunya, dengue virus, Zika virus, or as yet unrecognised pathogenic viruses transmitted by the same mosquito species.
Relying on an antivector vaccine is risky and a combined antipathogen and antivector vaccine approach is considered safer. However, as a first line of defence, an effective mosquito peptide vaccine could save lives and buy time to develop a targeted vaccine.9
1. Manning JE, Oliveira F, Countinho-Abreu IV. Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial. Lancet. 2020 doi: 10.1016/S0140-6736(20)31048-5. published online June 11. [PubMed] [CrossRef] [Google Scholar]
5. Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL. Vector transmission of Leishmania abrogates vaccine-induced protective immunity. PLoS Pathog. 2009;5 [PMC free article] [PubMed] [Google Scholar]
6. Reed SG, Coler RN, Mondal D, Kamhawi S, Valenzuela JG. Leishmania vaccine development: exploiting the host-vector-parasite interface. Expert Rev Vaccines. 2016;15:81–90. [PMC free article] [PubMed] [Google Scholar]
7. Oliveira F, Rowton E, Aslan H. A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates. Sci Transl Med. 2015;7 [PubMed] [Google Scholar]
9. Wang Y, Marin-Lopez A, Jiang J, Ledizet M, Fikrig E. Vaccination with Aedes aegypti agbr1 delays lethal mosquito-borne Zika virus infection in mice. Vaccines (Basel) 2020;8:e145. [PMC free article] [PubMed] [Google Scholar]
More information: Maria Lúcia Brito Ferreira et al, Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study, The Lancet Neurology (2020). DOI: 10.1016/S1474-4422(20)30232-5