**7. Challenges to RSV vaccine development**

*The Burden of Respiratory Syncytial Virus Infection in the Young*

At present, there is no approved vaccine is present in the market which can protect from RSV infection. Due to increased burden of disease, it is essential to develop a vaccine that can give protection against the disease [47]. Recently, a lot of RSV vaccine candidates have been emerged using a variety of advanced technologies. About 60 RSV vaccines candidates targeting the pediatric and older populations are in development stage and some are also in preclinical stage [62]. According

to a study, 16 RSV vaccine candidates are in clinical development stage [62].

continuing problem for live attenuated RSV vaccine [65–67].

There was no observation of enhanced disease occurrence [70–77].

RSV G and F glycoproteins lead to the induction of neutralizing antibodies. These have been evaluated as potential vaccine candidate [68]. Subunit vaccines have the potential to be used for maternal immunization. They are also useful candidates for elderly immunization. A number of subunit vaccines have been evaluated recently. The vaccines which are in clinical trials are co-purified G, F and M proteins; purified F glycoprotein (PFP-1, PFP-2 and PFP-3); and BBG2NA etc. [69–76]. RSV PFP-1, PFP-2 and PFP-3 are the candidates which have been evaluated in children of >12 months of age and also in elderly target populations. These vaccine candidates consist of purified glycoprotein which are adsorbed to Al(OH)3 (PFP-1 and PFP-2) or AlPO4 (PFP-3). These candidates were sufficiently tolerated by the target populations but acute reactions were also observed up-to minimum level.

During 1960s, after the failure of formalin inactivated RSV vaccine (FI-RSV), struggles were started to develop live-attenuated vaccines candidates. By serial passaging of RSV A2 strain at lower temperature, live attenuated vaccines were produced; however, it was hard to achieve the balance between immunogenicity

Today, a lot of the cold passage (cp) and temperature sensitive (ts) vaccines have been produced. Evaluation of one cpts-248/404 was done in 1–2 month old aged infants. But it led to the problem such as congestion of upper respiratory tract and so, it was not followed for more investigations. After this struggles were done to attenuate the cpts-248/404 strain and many mutants were produced. After evaluation these generated mutants were found to be over or under attenuated [63]. There is another live-attenuated type RSV vaccine which includes M-2 gene deletion is being tested on nonhuman primates. The M-2 gene regulates the transition from transcription to RNA replication. Studies have shown that by the deletion of M-2 gene, viral RNA replication is decreased but at the same time G and F protein expression is increased through transcription which means that virus is attenuated at adequate level and may lead to neutralizing antibody response [64]. NS2 is another target gene for producing live attenuated vaccine RSV NS2. gene increases the shedding of epithelial cells and reduces or inhibits the antiviral cellular type 1 IFN induction and IFN response of the host. Vaccines which include the deletion of NS2 gene are stable genetically and sensitive to temperature to some extent [65, 66]. SH gene also has been considered for deletion for the live attenuated vaccines. It is believed that SH gene is involved in viral fusion. According to few studies, it is involved in the inhibition of apoptosis by blocking the TNF- alpha pathway. To obtain the sufficient attenuation level to get the safety is the major

**6. Current status of RSV vaccine**

**6.1 Live attenuated vaccine**

and safety [62].

**6.2 Subunit vaccines**

**82**
