Syncytial Virus eosinophilia augmented.11,31


witnessed in the FI-RSV vaccinated children19


This was similar to the immunopathology and led to the conclusion


that the FI-RSV vaccine failed mainly because it primed the Th2 response against the virus.32


However, experiments in BALB/c mice showed that depletion of TNF-α from immunized mice significantly reduced their weight loss after the RSV challenge. TNF-α depletion decreased IFN-g production by CD4+ T cells, suggesting that exacerbated Th1 responses also contribute to systemic disease.18,33,35


A variety of host factors affect RSV disease


immunopathology and further research is needed to understand the immune mechanisms that lead to severe RSV disease.


Vaccine Development


Recent Progress in Respiratory Syncytial Virus Vaccine Development


Clinical experience with FI-RSV vaccine and the knowledge obtained from various animal models of RSV disease highlight some essential features required of an RSV vaccine, particularly in infants—for example, the vaccine must be able to generate high levels of protective neutralizing antibodies, CD8+ RSV-specific cytotoxic T cells and a balanced Th1/Th2 CD4+ T cell response similar to that evoked by wild-type RSV infection. Ideally, an effective vaccine should also be able to induce virus-specific secretory IgA in the respiratory mucosal area, because IgA is the first line of defense against infection of the upper respiratory tract. Obstacles to the development of neonatal vaccines include immaturity of the neonatal immune system and interference of the immune response owing to the presence of maternal antibodies.21


Although a vaccine against RSV is not yet available, significant progress has been made in recent years. A successful RSV vaccine should be able to avert serious RSV-associated lower respiratory tract illness with the primary targets being young infants, the immunocompromised and the elderly.17


Given that an RSV


vaccine would be given preferably to infants within the first six months, it is crucial that RSV vaccines harmonize with routine childhood vaccines. A variety of old and new vaccine formulations that have been studied to overcome the limiting factors that interfere with vaccine response, particularly in children, are reviewed below.


Live-attenuated RSV Vaccines


In a study looking at humoral immunity, infants and children developed strong antibody responses to both F and G proteins after natural infection with wild-type RSV infection, showing that both antigens should be represented in a live-attenuated vaccine. Young infants with low titers of maternally derived antibodies were shown to mount a substantial RSV-neutralizing antibody response under conditions in which the immunosuppressive effect of maternal


62


Currently, the most advanced studies in the direction of a safe and effective vaccine for use in infants lie with the development of a live-attenuated intranasal RSV vaccine. Live-attenuated vaccines administered by an intranasal route imitate natural infection. This could generate a balanced immune response, which is less likely to induce enhanced disease. Given that the concentrations of maternal antibodies that reach the mucosal surfaces are lower than serum concentrations, mucosal vaccines could be administered earlier during infancy compared with systemic vaccines, and could confer protection at a younger age.36


antibodies was diminished.37


Implications of this study include the


suggestion that a live-attenuated RSV vaccine given at intervals during the first six months of life would result in an increasing infant antibody response as the maternal antibodies disappear.37


Cold-passaged and Temperature-sensitive Respiratory Syncytial Virus vaccines


Two classes of attenuated viruses were developed that would only replicate at temperatures below 37ºC (i.e. at temperatures similar to those in the upper respiratory tract) and therefore were growth restricted at normal body temperatures.38


Two strategies to develop


these classes include serial viral passages to identify cold-passaged (cp) strains and chemical mutagenesis to generate RSV strains with temperature-sensitive (ts) phenotypes.39


Multiple promising cp and ts


RSV vaccine candidates were assessed in clinical trials, but were found to be either over or under attenuated. The first live attenuated RSV vaccine to progress to trials in infants as young as one month old was cpts 248/404. However, it caused significant nasal congestion that interfered with feeding and sleeping.40


Genetically Engineered Live-attenuated Vaccines To further attenuate the cpts vaccine, reverse genetics was used to add additional attenuating markers. Reverse genetics is a powerful way of introducing combined attenuating mutations or deletions in the RSV genome to produce vaccines that are sufficiently infectious and immunogenic, yet attenuated and genetically stable.41


Deletion


of a non-essential gene (e.g. SH, NS1, or NS2) combined with a known attenuating cp and ts mutation might produce a highly attenuated genetically stable vaccine.17


Currently, recombinant cpts


248/404/1030_SH (MEDI-559), which is an intranasal, recombinant, live-attenuated, ts RSV vaccine, is being developed by Medimmune in conjunction with the National Institute of Allergy and Infectious Disease (NIAID) and is currently being evaluated in healthy children between one and 24 months of age.40,42


Data from trials of RSV vaccine candidates


have shown that this intranasally given live-attenuated RSV is capable of replicating in the presence of maternal antibodies.43


Whether the


immune response induced by this vaccine is robust and durable enough to prevent wild-type RSV disease efficiently remains to be determined. However, this is the first vaccine candidate to be tested in the target infant population since the FI-RSV trials during the 1960s.44


Subunit Vaccines


Glycoproteins F and G characterize the major targets for the immune response against RSV and are the key subunit vaccine candidates. Both F and G proteins induce neutralizing antibodies, indicating that a subunit vaccine might confer protection against wild-type infection. Purified F protein subunit vaccines (PFP-1, PFP-2, and PFP-3) have been tested in several clinical trials.38


In both Phase I


and II studies, the vaccines were found to be safe and immunogenic in adults and children over 12 months old. However, some upper respiratory symptoms developed, and clinically relevant lower respiratory infections were not reduced by the vaccines.45


A PFP


vaccine was also evaluated in women in the third trimester of pregnancy as well as in elderly patients and children over one year old. Although there were no adverse effects, there was only a small increase in neutralizing antibody titers in mothers and infants.46


US RESPIRATORY DISEASE


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