RSV is the single most important cause of severe LRIs in infants and young children. RSV disease spectrum includes a wide array of respiratory symptoms, from rhinitis and otitis media to pneumonia and bronchiolitis, the latter two diseases being associated with substantial morbidity and mortality. Humans are the only known reservoir for RSV. Spread of the virus from contaminated nasal secretions occurs via large respiratory droplets, so close contact with an infected individual or contaminated surface is required for transmission. RSV can persist for several hours on toys or other objects, which explains the high rate of nosocomial RSV infections, particularly in paediatric wards.
The global annual infection and mortality figures for RSV are estimated to be 64 million and 160 000 respectively. In temperate climates, RSV is well documented as a cause of yearly winter epidemics of acute LRI, including bronchiolitis and pneumonia. In the USA nearly all children, by two years of age, have been infected with RSV, is estimated to be responsible for 18 000 to 75 000 hospitalizations and 90 to 1900 deaths annually. The incidence rate of RSV-associated LRI in otherwise healthy children was calculated as 37 per 1000 child-year in the first two years of life (45 per 1000 child-year in infants less than 6 months old) and the risk of hospitalization as 6 per 1000 child-years (11 per 1000 child-years in the first six months of life). Incidence is higher in children with cardio-pulmonary disease and in those born prematurely, who constitute almost half of RSV-related hospital admissions in the USA. Children who experience a more severe LRI caused by RSV later have an increased incidence of childhood asthma. These studies serve as a basis for anticipating widespread use of RSV vaccines in industrialized countries, where the costs of caring for patients with severe LRI and their sequelae are substantial. RSV also is increasingly recognized as a important cause of morbidity from influenza-like illness in the elderly.
Few population-based estimates of the incidence of RSV disease in developing countries are available, although existing data clearly indicate that, there also, the virus accounts for a high proportion of LRIs in children. Studies in Brazil, Colombia and Thailand show that RSV causes 20–30% of LRI cases in children from 1–4 years of age, a proportion similar to that in industrialized countries. In addition to accurate incidence rates, other important data for developing countries are lacking, such as the severity and case–fatality rates for RSV infection at the community level and the median age of first infection. Preliminary data from community-based studies suggest that the median age of first infection may vary between communities. This information is important for vaccination programme planners, when considering the optimal schedule for vaccination. For example, maternal immunization against RSV would be a desirable strategy to adopt if rates of infection during the first two months of life were found to be high.
Another confusing aspect of the epidemiology of RSV infection that may have an impact on vaccine use is the seasonality of the disease. In Europe and North America, RSV disease occurs as well-defined seasonal outbreaks during the winter and spring months. Studies in developing countries with temperate climates, such as Argentina and Pakistan, have shown a similar seasonal pattern. On the other hand, studies in tropical countries often have reported an increase in RSV in the rainy season but this has not been a constant finding. Indeed, marked differences in the seasonal occurrence of RSV disease have been reported from geographically contiguous regions, e.g. Mozambique and South Africa, or Bangladesh and India. Cultural and behavioral patterns in the community might affect the acquisition and spread of RSV infection. A clear understanding of the local epidemiology of the disease will be critical for the implementation of a successful vaccine development and introduction programme.
Virology
RSV belongs to the family Paramyxoviridae, subfamily Pneumovirinae, genus Pneumovirus. The genome of RSV is a 15,222 nucleotide-long, single-stranded, negative-sense RNA molecule whose tight association with the viral N protein forms a nucleocapsid wrapped inside the viral envelope. The latter contains virally encoded F, G and SH glycoproteins. The F and G glycoproteins are the only two components that induce RSV neutralizing antibody and therefore are of prime importance for vaccine development. The sequence of the F protein, which is responsible for fusion of the virus envelope with the target cell membrane, is highly conserved among RSV isolates. In contrast, that of the G protein, which is responsible for virus attachment, is relatively variable; two groups of RSV strains have been described, the A and B groups, based on differences in the antigenicity of the G glycoprotein. Current efforts are directed towards the development of a vaccine that will incorporate strains in both groups, or will be directed against the F protein.
Vaccine
Development of vaccines to prevent RSV infection have been complicated by the fact that host immune responses appear to play a role in the pathogenesis of the disease. Early studies in the 1960s showed that children vaccinated with a formalin-inactivated RSV vaccine suffered from more severe disease on subsequent exposure to the virus as compared to unvaccinated controls. These early trials resulted in the hospitalization of 80% of vaccinees and two deaths. The enhanced severity of disease has been reproduced in animal models and is thought to result from inadequate levels of serum-neutralizing antibodies, lack of local immunity, and excessive induction of a type 2 helper T-cell-like (Th2) immune response with pulmonary eosinophilia and increased production of IL-4 and IL-5 cytokines.
In addition, naturally acquired immunity to RSV is neither complete nor durable and recurrent infections occur frequently. In a study performed in Houston, Texas, it was found that 83% of the children who acquired RSV infection during their first year of life were reinfected during their second year, and 46% were reinfected during their third year. At least two thirds of these children also were infected with PIV-3 in their first two years of life. Older children and adults, however, usually are protected against RSV-related LRIs, suggesting that protection against severe disease develops after primary infection.
Passive immunization in the form of RSV-neutralizing immune globulin or humanized monoclonal antibodies given prophylactically has been shown to prevent RSV infection in newborns with underlying cardiopulmonary disease, particularly small, premature infants. This demonstrates that humoral antibody plays a major role in protection against disease. In general, secretory IgAs and serum antibodies appear to protect against infection of the upper and lower respiratory tracts, respectively, while T-cell immunity targeted to internal viral proteins appears to terminate viral infections. Although live attenuated vaccines seem preferable for immunization of naive infants than inactivated or subunit vaccines, the latter may be useful for immunization of the elderly and high-risk children, as well as for maternal immunization. Candidate vaccines based on purified F protein (PFP-1, -2 and -3) have been found safe and immunogenic in healthy adults and in children over 12 months of age, with or without underlying pulmonary disease, as well as in elderly subjects and in pregnant women. A Phase I study of PFP-2 was conducted in 35 women in the 30th to 40th week of pregnancy; the vaccine was well tolerated and induced RSV anti-F antibody titres that were persistently fourfold higher in newborns to vaccinated mothers than to those who had received a placebo. No increase in the frequency or morbidity of respiratory disease was observed in infants from vaccinated mothers. Maternal immunization using a PFP subunit vaccine would be an interesting strategy to protect infants younger than six months of age who respond poorly to vaccination.
The efficacy of a subunit PFP-3 vaccine was tested in a Phase III trial on 298 children 1 to 12 years of age with cystic fibrosis. The vaccine was well tolerated and induced a four-fold increase in RSV neutralizing antibody titres, but this was not associated with significant protection against LRI episodes as compared to placebo recipients.
A subunit vaccine consisting of co-purified F, G, and M proteins from RSV A has been tested in healthy adult volunteers in the presence of either alum or polyphosphazene (PCPP) as an adjuvant. Neutralizing antibody responses to RSV A and RSV B were detected in 76–93% of the vaccinees, but titres waned after one year, suggesting that annual immunization with this vaccine will be necessary.
A subunit approach also was investigated using the conserved central domain of the G protein of an RSV-A strain, whose sequence is relatively conserved among groups A and B viruses. A recombinant vaccine candidate, BBG2Na (Pierre Fabre), was developed by fusing this domain (G2Na) to the albumin-binding region (BB) of streptococcal protein G. The candidate vaccine elicited a protective immune response in animals, but was moderately immunogenic in adult human volunteers and its clinical development was interrupted due to the appearance of unexpected side effects (purpura) in a few immunized volunteers. Another RSV candidate vaccine is a synthetic peptide of the conserved region of the G protein administered intranasally, either alone or in combination with cholera toxin. Protection was conferred to mice even without the cholera toxin.
Live, attenuated RSV vaccines that could be delivered to the respiratory mucosa through intranasal immunization have been in development for more than a decade, based on temperature-sensitive (ts), cold-adapted (ca) or cold-passaged (cp) mutant strains of the virus. Difficulties for such a vaccine arise from over- or under-attenuation of the virus and limited genetic stability. Most attenuated live RSV strains tested in humans to date caused mild to moderate congestion in the upper respiratory tract of infants one to two months old and, therefore, were considered as insufficiently attenuated for early infancy. Recombinant RSV vaccines with deletion mutations in nonessential genes (SH, NS1 or NS2), and both cp and ts mutations in essential genes, are currently being evaluated.
Recombinant DNA technology also has provided the possibility of engineering a chimeric virus containing the genes of human PIV-3 surface glycoproteins F and NH, together with those of RSV glycoproteins F and G, in a bovine PIV-3 genetic background. A first candidate vaccine was found to be attenuated and to induce an immune response to both human PIV-3 and RSV in rhesus monkeys and should presently enter clinical trials. Similarly, a bovine PIV-3 genome was engineered to express human PIV-3 F and HN proteins and either native or soluble RSV protein F. Resulting recombinants induced RSV neutralizing antibodies and protective immunity against RSV challenge in African Green monkeys. These b/h PIV3/RSV F vaccines will presently be tested for safety and efficacy in human clinivcal trials as bivalent vaccines to protect infants from both RSV and PIV-3 infection and disease.
Finally, a combination of a live-attenuated vaccine with a subunit vaccine also is being considered for protecting adults against RSV illness, although a preliminary test of this strategy in healthy young and elderly adults was inconclusive.
Source: http://www.who.int/vaccine_research/diseases/ari/en/index3.html