A review of vaccines against the respiratory syncytial virus

By Nidhi Saha, BDSReviewed by Danielle Ellis, B.Sc.Nov 3 2022

Respiratory syncytial virus (RSV) causes respiratory ailments like pneumonia and bronchiolitis, mainly affecting children under five and the elderly above 65. 

The findings of a recent review published in Vacunas reviewed the epidemiology, molecular characteristics, populations affected by the virus, and vaccines against RSV.

Background

Every year RSV infects millions of children under five and the elderly above 65 years of age, causing millions of hospitalizations and thousands of deaths. The illness takes the form of an epidemic during winters. Almost every child experiences at least one episode of RSV infection by the age of three years; reinfections occur either annually or after every three-to-five years. 

This depicts the inadequacy of the immune system to confer long-term protection against the virus. Therefore, RSV vaccination is essential for pregnant women, children below two years of age (preferably immediately after attaining six months), and the senior population.

Molecular characteristics of RSV

RSV is an enveloped RNA virus belonging to the Pneumoviridae family with ten genes that encode 11 proteins. Proteins found in the viral envelope are small hydrophobic protein (SH), matrix protein (M), glycoprotein F (fusion), and attachment glycoprotein (G). Glycoprotein G and F confers infectivity to the virus; the former attaches the virus to the host cells, and the latter facilitates its entry into the cell and results in syncytia formation pathognomic to this illness. 

The G and F glycoproteins are of the immunodominant type, inducing neutralizing antibodies inside the host. Glycoprotein G has three varieties of epitopes – conserved (present in all strains), group-specific, and species-specific. The precursor of glycoprotein F is inactive and contains three hydrophobic peptides – a signal peptide, a transmembrane region, and a fusion peptide.

RSV has two subgroups, A and B, which circulate alternatively or together, differing antigenically by the glycoprotein G sequence. Hence, antibodies against glycoprotein G may be subtype-specific, whereas antibodies against glycoprotein F mostly have neutralizing activity against the two subgroups.

Generally, the F glycoprotein is used as the antigen for developing vaccines. This glycoprotein has two presentations (pre-fusion or pre-F and post-fusion or post-F). Among these, the antigenic site in pre-F (“site zero”) is the most potent inducer of neutralizing antibodies.

RSV vaccination

RSV evades the host immunity by multiple mechanisms, of which three have been recognized – conformational and anatomical evasion of the neutralizing antibodies and direct modulation of immunity. All of these should be accounted for during vaccine development.

The infection caused by RSV is self-limiting – humans are the only natural reservoir. The target vaccination population is children below six months and older and the elderly above 65.  

The developing immune system of infants is immature and unable to confer protection from exogenous antigens. Hence, this age group forms a priority population for RSV vaccination; monoclonal antibodies use is considered the apt choice. 

Vaccination of the mother during pregnancy is the best immunization option. In addition to the transplacental transfer of antibodies, immunoglobulin A transferred during breastfeeding confers protection to the infant. RSV usually affects children between six months to two years of age. Thus, infants and children between six months and five years of age constitute another target group; vaccination aims to limit viral circulation and its collateral effects.

The third target group is the senior population (65 years and above). Nearly 3-10% of all acute respiratory infections in this age group are caused by RSV, which amounts to nearly 250,000 hospitalizations and 14,000 deaths annually. Moreover, waning immunity and other underlying diseases predispose this population to respiratory infections.

Of note, mRNA vaccines are advantageous over others owing to their high safety profiles, highly-controllable antigen production with high antigenic identity, scalable and rapid production process, and production without cell cultures.

A non-replicative, conventional, cellular-like mRNA vaccine targeting RSV has been developed. These are of two types – unmodified mRNA and modified m RNA. These vaccines induce highly specific immune responses as they encode a single protein. However, high doses are necessary to induce sufficient efficacy. Further, to protect against rapid degradation and fragility, the mRNA molecules are encapsulated in complex lipid structures – known as lipid nanoparticles. 

Pre-fusion (pre-F) has better antigenic specificity and higher affinity potential as most neutralizing antibodies target the “zero site.” Therefore, antigens that protect and maintain this epitope are preferable.

Meanwhile, these vaccines pose minimal risk for side effects, barring the local reaction at the site of injection. Even the highest dose (300 μg) shows a low risk for adverse effects. Phase 1 trials confirm the immunogenicity and safety of NPL-m RNA vaccines, while the results of phase 2 trials are awaited.

Summary

This study reviewed the epidemiology, molecular characteristics, populations affected by the virus, and vaccines against RSV. Having only one reservoir makes it ideal for developing a vaccine against RSV. Most vaccines employ the glycoprotein F (Pre-fusion form) as an antigen. Recently, mRNA vaccines have been developed with promising antigenicity and efficacy. More studies are warranted to study the efficacy of m RNA vaccines against other viruses affecting the human population.