Respiratory Syncytial Virus Vaccine

5 Jun

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.

Random Posts

Comments are closed.