A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children

Human respiratory syncytial virus (HRSV) causing severe respiratory infection in infants and children’s belongs to pneumovirus genus in paramyxoviridae family. It is a negative-sense, single-stranded RNA viruses classified into HSRV-A (10 genotypes GA1-7, NA1-2 and SSA1) and HSRV-B (14 genotypes GB1-4, SAB1-3, and BA1-6) groups; have adaptive advantage over host immune system through mutation and nucleotide duplication. The 15kb genome of HSV containing 10 genes encodes for 11 proteins (NS1, NS2, N, M, P, G, F, SH, M2-1, M2-2 and L) sequentially from NS1 to L genes with two ORF for M2 protein (1). Within the host NS1 and NS2 inhibit type-I interferons (IFNs) signalling, M2-1 and M2-2 encodes matrix proteins required for virus assembly contains CD8 epitopes, SH, S and F encodes for viral coat and G is a surface glycoprotein, L encodes for RNA polymerase whereas P is a cofactor for L (1). In order to combat over RSV generated illness a live attenuated RSV vaccine has been considered as an attractive strategy for immunization of infants and children’s beyond their neonatal period. However administration of live attenuated RSV fails to induce sufficient immune response. In such case reverse genetics can laid the foundation of development of engineered virus. Matrix protein M2-2 is responsible for virus assembly, where its depletion restricts virus assembly or virus replication. In such a case enhanced transcription of viral genes elicits substantial humoral and cellular immune response against RSV infection (2). Karron et al investigated the vaccination impact of RSV deletion mutant RSVMEDI DM2-2 in 15 adults and children’s (15 sero positive and 30 seronegative); from PRNT (plaque reduction neutralization titer) MAARI (surveillance for medically attended acute respiratory illness) analysis it is factual that vaccination of DM2-2 strain restricts virus replication but competent enough in elicitation of higher RSV neutralizing serum antibody titer then any known vaccine enabling host to protect itself from seasonal infection of RSV (3). Over all the findings of Karron et al postulates that DM2-2 vaccination directed upregualtion in RSV neutralizing antibodies is due to enhanced gene transcription and antigen synthesis where absence of MAARI in RSV season is supporting the merits of MD2-2 over previously lead live attenuated RSV vaccine candidate RSVcp248/404/1030/DSH. Still the connection of adaptive and innate immune signalling is missing from investigation. It is warned to investigate what innate immune signalling is taking place during DM2-2 vaccination that is different from RSVcp248/404/1030/DSH. Furthermore there is clear cut requirement to demonstrate, what is the minimum age for vaccination for elicitation of highest protective effect of DM2-2 vaccine?

References

1. W. Leea, Y. Kima, D. Kimb, H. S. Leea, H. Y. Leea, K. Kima, Complete Genome Sequence of Human Respiratory Syncytial Virus Genotype A with a 72-Nucleotide Duplication in the Attachment Protein G Gene. J. Virol. 86, 13810-13811 (2012).

2. A. Bermingham, P. L. Collins, The M2–2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription. Proc. Natl. Acad. Sci. U.S.A. 96, 11259–11264 (1999).
3. R. A. Karron, C. Luongo, B. Thumar, K. M. Loehr, J. A. Englund, P. L. Collins, U. J. Buchholz, A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Sci. Transl. Med. 7, 312ra175 (2015).