Molecular Epidemiology of Rift Valley Fever Virus

Antoinette A. Grobbelaar, Jacqueline Weyer, Patricia A. Leman, Alan Kemp, Janusz T. Paweska, and Robert Swanepoel

Author affiliations: National Institute for Communicable Diseases of the National Health Service, Sandringham, South Africa (A.A. Grobbelaar, J. Weyer, P.A Leman, A. Kemp, J.T. Paweska, R. Swanepoel); University of Pretoria, Pretoria, South Africa (R. Swanepoel)

Abstract

Phylogenetic relationships were examined for 198 Rift Valley fever virus isolates and 5 derived strains obtained from various sources in Saudi Arabia and 16 countries in Africa during a 67-year period (1944–2010). A maximum-likelihood tree prepared with sequence data for a 490-nt section of the Gn glycoprotein gene showed that 95 unique sequences sorted into 15 lineages. A 2010 isolate from a patient in South Africa potentially exposed to co-infection with live animal vaccine and wild virus was a reassortant. The potential influence of large-scale use of live animal vaccine on evolution of Rift Valley fever virus is discussed.

Rift Valley fever (RVF) is an acute disease of domestic ruminants in Africa and the Arabian Peninsula. This disease is caused by a mosquito-borne virus of the family Bunyaviridae and genus Phlebovirus. Large outbreaks occur at irregular intervals when heavy rains favor breeding of mosquito vectors of the virus and are characterized by deaths of newborn animals and abortion in pregnant sheep, goats, and cattle. Humans become infected by contact with tissues of infected animals or from mosquito bites and usually show development of mildly to moderately severe febrile illness. However, severe complications, including ocular sequelae, encephalitis, and fatal hemorrhagic disease, occur in some patients (1).

Rift Valley fever virus (RVFV) has a negative-sense, single-stranded RNA genome comprising large (L), medium (M), and small (S) segments. The L segment encodes viral RNA polymerase. The M segment encodes envelope glycoproteins Gc and Gn, a nonstructural protein, and a 78-kDa fusion protein of nonstructural and Gn proteins. The S segment shows an ambisense strategy and encodes nucleocapsid protein N and a nonstructural protein (2).

Early genetic analysis involved nucleotide sequencing of M segment RNA fragments encoding glycoprotein that induced neutralizing antibody response in 22 isolates obtained over 34 years in 6 countries (3). This analysis showed remarkable stability of sections of the genome expected to be under greatest immune selection pressure. The diversity observed in isolates from Zimbabwe indicated that outbreaks do not invariably involve a single genotype of virus but can result from intensified transmission of multiple strains already circulating in RVF-endemic areas. Nevertheless, neutralization of isolates with monoclonal antibodies confirmed that a single vaccine should suffice to control the disease (3). Slightly greater variability was observed among isolates when nonstructural protein sequence data were analyzed (4). Partial sequences determined for all 3 RNA segments of the genome of 20 isolates sorted into 3 geographically linked lineages associated with western Africa, Egypt, and eastcentral Africa and showed evidence of reassortment of genome segments between some sub-Saharan isolates (5).

High-throughput technology facilitated whole-genome sequence analysis of 33 isolates and resulted in confirmation of low genetic diversity of the virus and separation of the isolates into 7 lineages. There was no mutually exclusive correlation between genotype and geographic origin; representatives of geographic areas tended to cluster, but isolates from distant locations occurred in each lineage, indicating continuous widespread dispersal of virus (6). The remarkable congruence of phylogenetic trees for the 3 genome segments suggested that reassortment was not common, but convergence of some lineages within genome segments implied that reassortment had played an evolutionary role in the history of RVFV. Bayesian analysis suggested that the time of divergence of RVFV isolates from a most recent common ancestor dated to 1880–1890, the colonial period when the introduction of large concentrations of susceptible sheep and cattle would have facilitated exploitation of a new niche by an unknown progenitor virus. The evolutionary rate of the virus was similar to that of other RNA viruses. Thus, low nucleotide diversity probably relates to recent derivation from a common ancestor rather than stability of the genome.

Whole-genome sequencing and Bayesian analysis of 31 isolates associated with the 2006–2007 outbreak of RVF in Kenya showed that 2 sublineages of virus had evolved separately before or during a large outbreak during 1997–1998, with continued expansion of 1 sublineage dating from 2–4 years before 2006, confirming that outbreaks in disease-endemic areas might be associated with multiple lineages of virus, and that virus activity and evolution can occur below the threshold of detection by public health or animal authorities during interepidemic periods (7). Other genetic studies have been more limited in scope and concerned with either locating and investigating mechanisms of pathogenicity or determining phylogenetic relationships of isolates involved in particular outbreaks (8–14).

Analysis of partial M segment sequence data for a large collection of isolates and derived strains obtained from various sources in Saudi Arabia and 16 countries in Africa during 1944–2010 showed phylogenetic relationships not apparent in studies involving a smaller range of isolates. A 2010 isolate from a patient in South Africa potentially exposed to co-infection with live animal vaccine and wild virus from a needle injury while vaccinating sheep plus selected other isolates were subjected to limited sequencing of all 3 segments of the genome to obtain evidence of reassortment. We present and discuss the epidemiologic implications of these findings.

Suggested citation for this article: Grobbelaar AA, Weyer J, Leman PA, Kemp A, Paweska JT, Swanepoel R. Molecular epidemiology of Rift Valley fever virus. Emerg Infect Dis [serial on the Internet]. 2011 Dec [date cited]. http://dx.doi.org/10.3201/eid1712.111035