Managing RSV

Unmet needs for managing RSV

There is no approved treatment for respiratory syncytial virus (RSV), and preventative therapies are limited to infants and children at high risk of severe RSV infections¹. There is an urgent requirement for preventative therapies that robustly protect vulnerable adult populations to reduce hospitalisations and mortality.

Unmet needs in RSV treatment

There are no approved treatments for RSV in children and adults who have severe infections

The antiviral drug ribavirin is used off-label for the treatment of life-threatening RSV in patients with dysfunctional immune systems^2,3. Ribavirin is restricted to this patient population as it is associated with toxicities affecting multiple body systems, including psychiatric and haematological effects³. Further, ribavirin has limited clinical evidence of efficacy in RSV; one study reported no efficacy in reducing admissions to intensive care, lengths of hospital stays, the use of ventilatory support, or mortality, while a second study showed that ribavirin reduced the likelihood of upper respiratory tract infections progressing to lower respiratory tract infections^2,4. Ribavirin must be administered as an aerosol for RSV infections, which also restricts its widespread use³.

Therefore, management of RSV infections is reliant on symptomatic relief of bronchiolitis, bronchitis and pneumonia⁵. Severely affected patients might need ventilatory support in intensive care². More targeted treatment options are needed to manage RSV.

Unmet needs in RSV prevention

There is only one prophylactic option for RSV, which is for use in infants and children only; there are no prophylactic options for adults

The prophylactic treatment, palivizumab, is indicated for the prophylaxis of RSV in infants and children who are at high risk of severe RSV infections.

Palivizumab is a monoclonal antibody that is administered by monthly intramuscular injection during the RSV season¹. This type of treatment is known as passive immunisation, as it supplies high-risk individuals with antibodies, but does not induce an immune response to RSV.

Palivizumab is indicated for use in¹:

• Premature infants (born ≤35 weeks) under the age of 6 months at the start of the RSV season
• Children less than 2 years of age who have required treatment for bronchopulmonary dysplasia (chronic lung disease) in the last 6 months
• Children less than 2 years of age with haemodynamically significant congenital heart disease

A systematic review has shown that palivizumab reduces rates of hospitalisation for RSV infection in these at-risk paediatric populations⁶.

More preventative therapies are needed, especially for high-risk adult populations¹.

RSV prevention in adults

As there are no preventative treatments for adults at risk of severe respiratory syncytial virus (RSV), ongoing vaccine trials may be of interest to clinicians involved in managing the burden of RSV².

Challenges of developing vaccines for older adults

One of the challenges of developing vaccines for older adult populations is that the aging immune system is not as responsive as that of younger populations⁷.

Vaccines developed for older people must be tailored to produce an immune response of an appropriate magnitude⁷

The main goal in adults is to deliver an appropriate dose of antigen to provoke a sufficient immune response⁷. Strategies to maximise the immune response to a vaccine could include the use of adjuvants (additives that boost the immune response to the antigen in the vaccine), the inclusion of multiple viral antigens or the delivery of booster vaccinations⁷.  

Adults aged over 65 years will also vary in the number of times they have been infected with RSV, which may affect immune responses to the vaccine⁷.

Vaccine strategies in adults

Several strategies may be used in the development of RSV vaccines.

Live-attenuated vaccines⁷

• Based on a live virus, but with a reduced ability to cause harm
• Effectiveness of live-attenuated viruses is based on pre-existing immunity

Recombinant vector vaccines^5,7,8

• Utilise a different type of non-harmful virus, such as the adenovirus, as a vector to transport portions of target DNA from the virus of choice
• Following vaccination, the target DNA is translated into an antigen, which provokes an immune response
• The adenovirus vector may also possess adjuvant properties, boosting the immune response in older people

Subunit vaccines^7,8

• Comprise purified, antigenic proteins of the virus only
• Allow delivery of a higher antigen dose compared with whole-virus, so may be appropriate for use in older adults

Nanoparticle vaccines^7–9

• Use virus-like particles or vesicles to deliver viral proteins, or DNA or messenger RNA (mRNA) that is converted to antigens by the vaccinated person
• mRNA vaccines for COVID-19 provoke similarly sized immune responses in adults of all ages

RSV antigens in investigational vaccines

The majority of investigational vaccines are based on the F protein of RSV⁵. The F protein is present on the surface of RSV, and in comparison with the G protein, the F protein is much less variable^5,7,10.

The structure of the F protein changes once it fuses to the cells of a human host; the different forms are termed prefusion F and postfusion F. The immune response is greater against prefusion F than postfusion F, so investigational vaccines tend to focus on the prefusion F structure to provide optimal protection against RSV infection^5,7.

The inclusion of other antigens of RSV, such as the G protein, M2-1 protein and N protein within a vaccine can bolster the immune response.

Investigational RSV vaccines in older adults

Several Phase II and Phase III clinical trials of RSV vaccines in adults aged 60 years or over are currently ongoing or have completed (Table 1). These vaccines are based on several of the RSV protein components (Figure 1). Studies in other populations, such as children and pregnant women, are also ongoing^2,8.

Figure 1. RSV protein targets for investigational vaccines in adults aged over 60 and investigational antivirals⁷. RSV, respiratory syncytial virus

Table 1. RSV vaccine trials in adults aged 60 years or over. Individual trials do not incorporate multiple RSV vaccines and data shown are not intended to be compared across studies^5,7,11–19. AE, adverse event; RSV, respiratory syncytial virus.

A key requirement of vaccines for older people is the need to overcome the reduced immune response in comparison with younger populations.

Indeed, the investigational GSK3844766A vaccine has shown similar responses across adults of all ages, indicating that the reduced immune responses in older people can be overcome¹⁴.

The investigational Ad26.RSV.preF vaccine has shown that symptom onset and severity can be reduced; initial data are from a single RSV season, but these results indicate that the reported immune responses to vaccines do translate into a positive symptom-based outcome¹².

Larger studies may be needed to identify vaccines that reduce RSV hospitalisations and mortality, and to determine the most effective dosing schedules

As vaccine trials continue, it will also be important to consider the timing of the vaccination and the need for boosters to ensure adequate protection during the RSV season⁷. The seasonality of RSV also raises a requirement to consider the timing of RSV vaccinations alongside other seasonal vaccinations, such as that for influenza. While cohort sizes for RSV and influenza trials are small, and additional noninferiority studies are required for approval of coadministration of RSV and influenza vaccines, larger studies are ongoing⁵. As the impact of RSV is similar to or greater than that of influenza, and both infections are seasonal, a combined approach to vaccination may be appropriate^20–23.

The RSV season

As the RSV vaccine landscape develops, new vaccines might emerge to prevent severe RSV infection in adults, as palivizumab does for infants and children

Treating RSV infections

Treatment goals for respiratory syncytial virus (RSV) are to relieve symptoms, reduce the time until symptoms are resolved, reduce viral load and limit transmission².

Current management strategies for RSV

As there is no licensed treatment for RSV, and the use of ribavirin is restricted to immunocompromised patients, most patients with RSV will only receive measures to manage symptoms^2,3

The symptomatic management of the outcomes of RSV – bronchiolitis and pneumonia - may occur at home in mild cases, and involves^24,25:

• Hydration
• Relief of fever with antipyretics
• Pain relief
• Saline nasal drops for infants and children

Severe cases of RSV require acute treatment in a hospital or intensive care setting, with intravenous fluids, supplementary oxygen, ventilatory support and suctioning of the airways^2,24–26. Patients may also be treated with antibiotics in the absence of a diagnosis of RSV^27,28.

As these treatments do not target the cause of the infection, there is a need for novel antiviral therapies that are suitable for use across a broad patient spectrum.

Investigational antivirals in adults

A number of investigational antiviral therapies are in development, which can be classified as^2,3:

• Fusion inhibitors
  • Target entry of RSV into host cells and fusion of RSV-infected cells with healthy neighbouring cells
• Replication inhibitors
  • Target replication of RSV and the assembly of new viruses within host cells

As with vaccines, most antivirals in development target the F protein of RSV, as it is less variable than the other component proteins of RSV (Figure 2)². Other targets include the L protein, and the N protein, which have roles in replication^29,30.

Figure 2. RSV protein targets for investigational antivirals⁷. RSV, respiratory syncytial virus.

Investigational antiviral treatments in clinical trials have only demonstrated efficacy when initiated prior to symptom development. As RSV progresses through the respiratory tract, it may become more difficult for antiviral drugs to have a positive impact on infected cells².

Five investigational oral antivirals and one investigational inhaled antiviral have recently completed or are currently in Phase II trials in adults (Table 2). Studies in other populations, including infants, are also ongoing².

The investigational drugs listed in Table 2 are not yet at the Phase III clinical trial stage and so it may be some time until the drugs are available to patients in routine practice

Table 2. Investigational antivirals for RSV in adults. Individual trials do not incorporate multiple antivirals and data shown are not intended to be compared across studies^31–40. AE, adverse event; LRTI, lower respiratory tract infection; RSV, respiratory syncytial virus; SAE, serious adverse event; URTI, upper respiratory tract infection.

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