Respiratory Syncytial Virus Immunopathology and Vaccine Development


The other subunit vaccine candidate, BBG2Na, involves a peptide from the G glycoprotein conjugated to the aluminum-binding domain of the streptococcal protein G. This was tested in a phase I trial in healthy adults and was shown to be safe and immunogenic. However, when evaluated in newborn macaques, IL-13-producing T cells as well as low pulmonary eosinophila were detected in two out of four vaccinated animals.47


120 healthy adults aged 18–40 were randomized to receive a single intranasal dose of MEDI-534 at various titers. In these adults, the vaccine was found to be highly restricted in replication, did not boost RSV and PIV3 antibody tiers, and produced no significant vaccine-related adverse effects.55


MEDI-534 was recently evaluated for


This shows that an RSV vaccine that is effective in adults might not be so in infants. Adjuvants that would increase the Th1 component of the immune response when given with RSV subunit vaccines are ideal. Subunit vaccines have the advantage of safety, but must be formulated and delivered with the appropriate adjuvant to induce the desired magnitude and quality of the immune response.21 The clinical activity and safety profile of RSV subunit vaccines have not yet been evaluated in RSV-naïve infants or young children.40


Vectored Vaccines


Viral vectors are known to provoke immune responses that are similar to those induced by natural infection. The ability of live replicating vectors, such as adenovirus, to induce adult-like responses makes them appealing for infant vaccines. Recently, Kim et al. developed a recombinant adenovirus-based vaccine candidate that induces an RSV-specific immune response and confers protective immunity against RSV in a murine model by a single intranasal immunization.48 The vaccine did not induce any detectable serum Ig or T cell response, suggesting that F-specific mucosal IgA is effective in preventing RSV infection. A single intranasal immunization with the vaccine rAd/F1co (recombinant replication-deficient adenovirus-based vaccine expressing F1 fragment of the F protein) provided effective immunization against future RSV challenge.48


Newcastle disease virus (NDV) and Sendai virus (SeV) are other negative-stranded RNA viruses that have been engineered to express the major RSV protective antigens F and/or G.49,50


Murawski et al. have


developed a virus-like particle (VLP) vaccine candidate made from the NDV hemagluttinin-neuraminidase protein and the ectodomain of the human RSV G protein.51


VLPs are nonreplicating, noninfectious


particles derived from virus-encoded proteins. Immunization in BALB/c mice induced neutralizing titers and, on subsequent RSV challenge, murine lungs showed no immunopathology.51


SeV, which is a murine


paramyxovirus, is being studied as a vector expressing the RSV F protein. The recombinant SeV-RSV F vaccine induced RSV-neutralizing antibodies, RSV-specific cytotoxic T lymphocytes and protected cotton rats and mice against challenge with RSV of both A and B subgroups.52


the first time in 120 healthy RSV- or PIV3-seropositive children aged between one and nine years. The vaccine safety profile was similar to that of the placebo, no viral shedding was detected and the vaccine was minimally immunogenic. The most frequent reported side effects included a runny nose, cough, sore throat, headache and fever, which were reported at similar frequencies in the placebo group.53


Given these


results, the vaccine is currently being tested in two studies: in healthy children between six and 24 month of age and in two-month-old infants.


Live Recombinant Vaccines


Live recombinant vaccines were first evaluated in BALB/c mice with recombinant vaccinia virus (vv) expressing RSV proteins. In BALB/c mice treated with a recombinant vv expressing the G protein of RSV, pulmonary eosinophilia characterized by a Th2 response was observed and was similar to that seen in mice vaccinated with the FI-RSV vaccine. These recombinants were found to be poorly immunogenic when given parenterally to chimpanzees, and were not considered suitable for vaccination against RSV.4,41


DNA Vaccines


DNA vaccination could be an efficient way of inducing CD8+ T cell responses, although these are weaker than those induced by live vectors. Advantages of DNA vaccines include the ability to give and express the vaccine antigens endogenously.41


However, they do not


appear to be immunogenic in humans and require multiple booster immunizations. DNA immunization also carries the risk of inducing autoimmune responses, as well as developing tolerance to the delivered antigen.40


Maternal Immunization


The goal of maternal immunization is to boost serum neutralizing antibodies in the mother during the second or third trimester of pregnancy, which in turn would enhance the active placental transport of serum neutralizing antibodies from the mother to the fetus.56


Infants


born before or during the RSV season with higher serum neutralizing antibodies against RSV should be better protected against severe RSV illness. The PFP-2 subunit vaccine was only found to be slightly immunogenic in healthy pregnant women.46


With a vaccine that can


However, both of these vaccine candidates have yet to be studied for their efficacy and safety profile in young children, particularly infants.


The vaccine, given intranasally, is a live-attenuated vaccine against both RSV and PIV3 that was previously shown to be immunogenic and to protect rodents and African green monkeys from wild-type RSV challenge.54


In a double-blind, placebo-controlled trial, US RESPIRATORY DISEASE


A promising viral vector vaccine currently being studied is MEDI-534, a derivative of a recombinant bovine/human (b/h) PIV3 vaccine that was evaluated against human parainfluenza 3 (hPIV3) infections. It is a chimeric b/hPIV3 structure that expresses the hPIV3 fusion, the hPIV3 hemagglutinin-neuraminidase and the RSV F proteins from a bPIV3 viral genome.53


elicit a better immune response, this approach might be a way of protecting infants during the RSV season.


Conclusion


Despite the results from the FI-RSV vaccine trials during the 1960s, dedicated and intense research has generated several promising candidate vaccines and an enhanced understanding of RSV. A thorough knowledge of the host response and molecular pathogenesis of RSV infection is essential for vaccine development. Both Th1 and Th2 CD4+ T cell responses, as well as the CD8+ T cell response, can have a vital role not only in protection against RSV infection, but also in vaccine-enhanced disease. Therefore, an RSV vaccine that generates a balanced immune response is likely to be most beneficial. n


63


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84