Effective Vaccine for Lassa Fever

Abstract

Lassa fever has been estimated to cause 5,000 deaths annually in West Africa. Recently, war in the zone where Lassa fever is hyperendemic has severely impeded control and treatment. Vaccination is the most viable control measure. There is no correlation between antibody levels and outcome in human patients, and inactivated vaccines produce high titers of antibodies to all viral proteins but do not prevent virus replication and death in nonhuman primates. Accordingly, we vaccinated 44 macaques with vaccinia virus-expressed Lassa virus structural proteins separately and in combination, with the object of inducing a predominantly TH1-type immune response. Following Lassa virus challenge, all unvaccinated animals died (0% survival). Nine of 10 animals vaccinated with all proteins survived (90% survival). Although no animals that received full-length glycoprotein alone had a high titer of antibody, 17 of 19 survived challenge (88%). In contrast, all animals vaccinated with nucleoprotein developed high titers of antibody but 12 of 15 died (20% survival). All animals vaccinated with single glycoproteins, G1 or G2, died, but all those that received both single glycoproteins (G1 plus G2) at separate sites survived, showing that both glycoproteins are independently important in protection. Neither group had demonstrable antibody levels prior to challenge. We demonstrate that in primates, immune responses to epitopes on both glycoproteins are required to protect against lethal challenge with Lassa virus without having untoward side effects and that this protection is likely to be primarily cell mediated. We show that an effective, safe vaccine against Lassa virus can and should be made and that its evaluation for human populations is a matter of humanitarian priority.Lassa virus is endemic in rural West Africa. The prevalence of antibody to Lassa virus ranges from 5% in Guinea and 15 to 20% in Sierra Leone and Liberia to over 20% in Nigeria (7,30). Lassa fever has been estimated to cause from 100,000 to 300,000 infections a year and several thousand deaths (30). The fatality rate for hospitalized patients is about 17%, but in certain groups of patients, such as pregnant women in their third trimester, more than 30% may die, and fetal or neonatal loss is about 88% (34). Deafness is a common complication of Lassa fever, affecting as many as 15% of patients and rendering an estimated 1 to 2% of the population hearing impaired in areas with high rates of infection (11). Treatment with intravenous ribavirin has been shown to be effective; however, it is not widely available in the areas where the disease is endemic and must be administered in the first week of illness for optimal efficacy (28). Recently, social and economic conditions have deteriorated in areas of high endemicity of eastern Sierra Leone and Liberia, and incidence and mortality have increased (R. Allan, R. Ladbury, K. Skinner, and S. Mardel, Abstr. Int. Conf. Emerg. Infect. Dis., abstr. 16, p. 21, 1998).Lassa virus, an arenavirus, exhibits persistent, asymptomat...

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

“…Every year, Lassa fever and the South American hemorrhagic fever viruses account for almost half a million cases worldwide, with approximately 16% mortality (Jahrling et al 1985, McCormick et al 1986, Fisher-Hoch et al 2000. Although rodents serve as a reservoir for arenaviruses, studies of hemorrhagic fever have relied on guinea pig, hamster and primate models rather than mouse models because the disease mechanism is fundamentally different in non-reservoir species (Peters et al 1987).…”

Combinatorial Ribavirin and Interferon Alfacon-1 Therapy of Acute Arenaviral Disease in Hamsters

“…In West Africa, infection with the Old World arenavirus, Lassa, by far has had the greatest impact on public health by haemorrhagic fever of arenaviral origin killing an estimated 5,000 people per year (Fisher-Hoch et al, 2000). A growing number of New World arenaviruses ( Junin, Machupo, Guanarito and Sabia) can also cause severe and often fatal haemorrhagic disease in humans (Charrel & de Lamballerie, 2003).…”

Lassa Virus Infection of Human Dendritic Cells and Macrophages Is Productive but Fails to Activate Cells

“…Humoral responses cannot control viral replication and the appearance of specific IgG in patients and infected monkeys is not correlated with recovery (11,12). The induction of cellular responses specific for viral glycoproteins protects nonhuman primates from a lethal challenge (12), and memory CD4 ϩ T cell responses against NP have been demonstrated in seropositive endemic subjects (13).…”