Essay on Respiratory Syncytial Virus Treatment

RSV Infection

Respiratory syncytial virus is the leading cause of severe lower respiratory tract disease in infants and young children worldwide. The estimated global annual burden of infections and mortality due to RSV are 33 million and 59,600, respectively (Shi et al., 2017). Premature infants, infants under six months, children younger than two years and those with congenital cardiovascular disease are at high risk of severe RSV illness. There has been previous research such as Hoover, Eades, and Lam (2018), that states in majority of cases where intubation is required in children, there were serious comorbidities including low birth weight, chromosomal abnormalities among others. In this study, Inhaled ribavirin, was identified as the only drug that has been FDA approved for the treatment of RSV (Hoover et al., 2018), however, while this treatment is effective for cases with severe RSV who have been placed on a mechanical ventilator, the AAP (American Academy of Pediatrics) removed this treatment from their guidelines for managing RSV. (Hoover et al., 2018).    

Older adults and those with impaired immunity or cardiovascular disease are also at high risk of respiratory syncytial virus infection. In the US, the estimated annual burden of respiratory syncytial virus hospitalization and mortality among elderly are 177,000 and 14,000 respectively (“CDC,” 2018). Ambrosch et. Al., (2018) argued that recent research shows RSV to be a recurrent pathogen that affects some adults with complicated infections.

Patients usually present with mild upper respiratory tract symptoms (runny nose, cough), but some may develop severe bronchiolitis and pneumonia symptoms (tachypnea, crackles, wheezing). Samples are generally collected in the form of nasopharyngeal swabs, sputum, or blood and then tested for the virus (Razanajatovo et al., 2018). There is an increasing trend that leads researchers to believe more deaths related to RSV infections are observed in developing countries compared to developed countries where there is access to intensive supporting care.

RSV has a lipoprotein coat and a single strand RNA part of the paramyxoviridae family, it encodes 11 proteins including; the attachment (G), small hydrophobic (SH), fusion (F), nucleoprotein (N), phosphoprotein (P), polymerase (L), matrix proteins (M1, M2-1, M2-2) and two non-structural proteins (NS1, NS2) (Clark & Guerrero-Plata, 2017). It is divided into 2 subtypes; Subtype A and Subtype B. Subtype A causes the severe clinical illnesses while Subtype B is the asymptomatic strain.

RSV can spread by direct contact like kissing an infected person, contact with a surface touching a doorknob then touching your face or by droplet like coughing or sneezing. RSV can survive for many hours on surfaces and RSV infected people are usually contagious for some days. The fusion (F) and attachment (G) surface glycoproteins help by creating neutralizing antibodies. This virus is seasonal and can affect different regions in different ways. In temperate regions, it generally affecting patients between late fall and early spring and can last between three and four months in any infected community. In tropical regions, on the other hand, it isn’t seasonal and can affect patients at any time and during any season (Higgins et al., 2016).

Daycare facilities, schools, crowded places, and low socioeconomic status increase the risk of acquiring RSV infection. RSV season usually occurs during the winter, depending on the region. In tropical countries, it increases during any and all seasons.

RSV is a virus that infects the central nervous system and can result in neurological symptoms such as drowsiness, convulsions, and epilepsy (Yuan et al., 2018). It is also mentioned that 40% of RSV-positive patients present with acute neurological symptoms before age 2.

In a study done by, Yuan et al., (2018) examined two groups and infected and non-infected group and then monitored these RSV viral titers. They found that the RSV long strain can easily and very quickly infect N2a neuronal cells and can stimulate co-localization or spatial overlap of the RSV F protein with TLR4 and nucleolin.

As with any disease/infection vaccines are the most cost-effective health intervention, however, to this day there are no FDA approved vaccinations for RSV. Currently, there are 60 RSV vaccines being developed and 16 of those are now in Phase 1-3 of trials (Higgins, Trujillo, & Keech 2016). Treatments used in the past for severe cases are no longer recommended in many countries because they were not proven have a high benefit in randomized controlled trials (Higgins et al., 2016).

In the 1960s the first vaccine for RSV was developed and administered in three doses. Researchers noticed that there was illness that occurred due to the vaccine because it failed to induce an adequate response of neutralizing antibodies and resistance to infection (Clark & Guerrero-Plata, 2017). It was noted that severe lung inflammation, worsened disease, and deaths occurred in the vaccinated seronegative infants. Immunizing older children with the FI-RSV didn’t have the same results because prior infection had primed their immune response (Higgins et al., 2016).

Researchers like Higgins et al., (2016) take into effect the economic burden it takes to developing vaccines and discuss approaches to develop vaccines for low-middle income country markets. Some of the newer vaccine approaches include M2-2 deletion mutation which instead of using replication utilizes transcription of the genome, which in effect leads to a higher production of proteins while limiting virus production. Protein-based vaccines have also been developed for protecting the elderly. Particle and protein-subunit vaccines are being developed to immunization during pregnancy to boost immunity and to increase the transfer of the RSV-specific antibody from mother to infant. MVA vectors, (modified vaccinia virus Ankara) express surface proteins that are processed by MHC class I and II pathways producing strong humoral and cellular immunity. Nucleic acid vaccines use plasmid DNA or messenger RNA encoding RSV antigens these vaccines are being developed with both the elderly and pediatric populations in mind. Another important vaccine development is the modification of the D25 mAb, genetic modifications that increase potency and half-life can even lead to protection from RSV with one dose for an entire season (Higgins et al., 2016).

In the last couple of decades, researchers have been working on several promising RSV vaccines. Some of these vaccines are now undergoing different phases of trials, and so far, they do not appear to cause the same issues as the 1960s vaccine. It has been shown that MN patches are effective in influenza vaccinations, Park et al., (2018), discuss another proposed solution to vaccine development for RSV. They discuss Microneedle (MN) patches which contain micron-scale solid needles that are coated with the vaccine. It is reported that this method has a better efficacy than the (IM) intramuscular needle method in that research shows MN produces a longer-lasting immune response and is stronger.

Research was done by Park et al., (2018) supports previously stated results revealing initial injectable FI-RSV IM vaccines failed previously because it led to vaccine-enhanced respiratory disease. They stated that as it is widely reported that the FI-RSV vaccine in mice resulted in vaccine-enhanced lung inflammation. They used this information to test whether the delivery method and the addition of MPL would have more favorable results. They concluded that immunogenicity and protective efficacy of RSV vaccines would definitely be improved if the vaccine was delivered using MN patch in addition to the MPL.

According to Higgins et al., (2016) there has been a great success with the RSV F mAb which is pushing scientists into the belief that developing a vaccine that produces functional antibody responses. Researchers have found that there is a high effectiveness of palivizumab and motavizumab in binding to antigenic site II on the RSV F protein, which has led many vaccine developers to put the majority of their focus on RSV F as a primary immunogen.

 Park et al., (2018) state similar to previous research discussed that Formalin-inactivated whole RSV vaccine (FI-RSV) failed and resulted in a hospitalization rate of 80% and two deaths in vaccinated children younger than two years of age. Toll-like receptor (TLR) like monophosphoryl lipid A (MPL) was reported to modulate liposome RSV vaccine immune responses, leading to a reduction in inflammation of the lungs.

Park et al., (2018) propose that if scientists were to develop an RSV vaccination via MN this would be highly attractive because the majority of affected patients are young children and infants and the elderly population a non-invasive delivery method would be better for those children with needle phobias. They also go so far as to mention that the MN patch vaccine would introduce a different profile of immune response that could prove to be more effective in preventing RSV vaccine-enhanced disease due to targeted skin dendritic cells. It is considered in this study that a patch-based skin delivery vaccine would be highly effective and is potentially self-applicable, safer and more effective than any other method of delivery.

The RSV infection can affect a wide array of victims including our most vulnerable populations, infants, young children, and adults. So, it is very important for researchers to develop effective vaccines to prevent the occurrence of the disease and we have seen this issue move high up on the agenda of developers for several decades now. The challenge that faces developers of this vaccine is that this virus has an inability to trigger a protective memory which has made several vaccines ineffective. Also, researchers have to be very cautious in clinical trials to avoid results similar to those of the 1966 vaccine clinical trials.

Clark and Guerrero-Plata, (2017) proposed solutions like innovations in the gene editing field has allowed for more specific live attenuated vaccines, more possible recombinant proteins for subunit vaccines, and an ample variety of possible chimeric vaccines. They also discuss the development of micro and nanoparticles and how these could open the door to more specific manipulations of the type of adaptive immune response desired. It is these new approaches and innovations that will inevitably result in the development of a reliable vaccine for all target populations.

References

• Ambrosch, A., Klinger, A., Luber, D., Arp, C., Lepiorz, M., Schroll, S., & Klawonn, F. (2018). [Clinical Characteristics and Course of Infections by Influenza A- and Respiratory Syncytial Virus (RSV) in Hospitalized Adults]. Deutsche Medizinische Wochenschrift (1946), 143(9), e68–e75. https://doi-org.mutex.gmu.edu/10.1055/s-0044-102004
• Clark, C. M., & Guerrero-Plata, A. (2017). Respiratory Syncytial Virus Vaccine Approaches: a Current Overview. Current clinical microbiology reports, 4, 202-207.
• Higgins, D., Trujillo, C., & Keech, C. (2016). Advances in RSV vaccine research and development – A global agenda. Vaccine, 34(26), 2870-2875. doi:http://dx.doi.org.mutex.gmu.edu/10.1016/j.vaccine.2016.03.109
• Hoover, J., Eades, S., & Lam, W. M. (2018). Pediatric Antiviral Stewardship: Defining the Potential Role of Ribavirin in Respiratory Syncytial Virus-Associated Lower Respiratory Illness. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 23(5), 372-378.
• Park, S., Lee, Y., Kwon, Y. M., Lee, Y. T., Kim, K. H., Ko, E. J., Jung, J. H., Song, M., Graham, B., Prausnitz, M. R., & Kang, S. M. (2018). Vaccination by microneedle patch with inactivated respiratory syncytial virus and monophosphoryl lipid A enhances the protective efficacy and diminishes inflammatory disease after challenge. PloS one, 13(10), e0205071. doi:10.1371/journal.pone.0205071
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