Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection in infants and young children which results in nearly 100,000 hospitaliza- tions and 4500 dead in the United States each year (295).
Premature infants and those with chronic lung disease or congential heart disease are most susceptible, as are bone-mar- row transplant recipients and the elderly (296–302). RSV epi- demics are thought to be fueled by reinfection with RSV and incomplete immunity from RSV (303). More information on RSV may be obtained in Chapter 3. To meet the challenge of providing some type of immunization to the very weak (prema- ture newborns), the immunologically challenged (transplant recipients), and the elderly, unique mechanisms of innoculation must be encouraged. For example, many newborns retain some maternal immunity. Therefore, a safe carrier of RSV vaccine to the mother prior to or during pregnancy might provide more resistance to RSV in the newborn. Vaccinating a newborn with traditional administration routes could be difﬁcult; and it must be determined when to administer the vaccine to an already-at- risk premature infant. Also, a proposed nasal spray vaccine has the potential to induce better mucosal immunity with less trauma than from the innoculation (295).
Formalin-inactivated vaccines. Development of a for- malin-inactivated (FI) vaccine suffered several set-backs in the 1960s when clinical trials led to severe, unex- pected illnesses associated with exposure to wild-type RSV (304,305). There was one observation, however, that older children vaccinated with FI-RSV did not de- velop wild-type RSV later. This suggested that the older children had had a previous wild-type infection. A live RSV vaccine may be more effective by reducing the risk of subsequent disease as seen in the FI-RSV vaccine. Difﬁculties with the FI-RSV suggest that a successful vaccine should induce sufﬁcient levels of neutralizing antibody, CD8+ RSV T-cells, and CD4 responses that are similar to the proﬁle of those stimulated by wild- type RSV. One thought has been to combine a non- replicating vaccine with unique adjuvants or cytokines to achieve a better immunologic status. (306,307).
Live-attenuated RSV vaccines. A variety of strategies for a live-attenuated vaccine led to investigations of multiple host range mutants, cold-passaged mutants, and temperature-sensitive mutants. Problems associ- ated with the temperature sensitive mutants and the cold-passaged mutants were reversions to the wild- type virus, overattenuation, and underattentuation. If live-attenuated vaccines are delivered intranasally, there is the potential for both local mucosal and sys- temic immunity that should protect against upper and lower respiratory tract disease. However, progress in the understanding of immunity to wild-type virus vac- cine versus live-attenuated virus vaccine has led to the current cold-passaged, temperature-sensitive vaccine. One particular candidate, cpts-248/404, has been shown to be safe and immunogenic in children older than 6 months, but led to nasal congestion in infants 1–2 months of age (308). Additional live-attenuated vaccine candidates are currently under evaluation in animal models with some promising results (212). Advanced technologies may be able to provide live-attenuated vac- cines which are genetically engineered (309).
cDNA clones of RSV. The discovery that cDNA could produce infectious virus meant that the viral genome has the capability to be manipulated (310). By intro- ducing single mutations into cDNA and evaluating the results in vitro, recombinant gene technology could de- lete a nonessential gene (such as the SH glycoprotein) or insert an additional gene.
Sub-unit vaccines. The genome for RSV has 10 genes that encode 22 proteins. The two major surface glyco- proteins are a fusion protein (F) and an attachment glycoprotein (G). In animal models subunit vaccines consisting of puriﬁed RSV glycoproteins are another promising avenue for RSV immunizations. Two sepa- rate puriﬁed F subunit protein vaccines have demon- strated efﬁcacy and safety in clinical trials involving healthy adults, elderly subjects, RSV-seropositive chil- dren over 12 months of age, and children with pulmo- nary disease (311–317). Further clinical studies are planned. A subunit vaccine with the G protein frag- ment of RSV-A is also under investigation (212). A pu- riﬁed F protein subunit was recently evaluated and found to reduce the overall incidence of RSV infections, but further testing is needed (318). Subunit vaccines would be very useful if they could be used to immunize pregnant women to enhance the protection of their newborns and in other high risk groups.