Pneumonia remains a serious worldwide problem, especially among the young, elderly, and immunocompromised. Over 900,000 children die each year due to the disease, and respiratory syncytial virus (RSV) is the most common viral cause (Streptococcus pneumoniae and Haemophilus influenzae type b being the most common bacterial causes). Antibiotics and antivirals can help treat sick patients, but prevention remains the ideal route of protection. Scientists are hard at work generating vaccine candidates, and a promising lead in an RSV vaccine has recently been published in Clinical and Vaccine Immunology.
Generating a microbial-mimicking antigen is a vital part of designing a good vaccine. The immune system may react differently to a protein in solution from a protein surrounded by a lipid bilayer; even the lipid makeup may influence how the immune system “sees” the embedded protein. A change in antigen presentation can determine whether the immune response is Th1-dominant or Th2-dominant, as well as the degree to which the response is mounted.
RSV is an enveloped (-)RNA virus, which means the first encounter of the immune system with an invading virion will be with its lipid membrane and embedded glycoproteins. One of these glycoproteins, the F protein, decorates the outside of the viral envelope (see schematic, left), and is one of the first viral proteins encountered by the immune system. Because of its location and role during infection, the F protein has been the subject of many potential vaccine studies. This latest study looks at how F protein conformation affects its safety and efficacy during immunization.
The F protein has different conformations at different points during infection, with both a stable postfusion conformation and a mid-level stable prefusion conformation. Antibodies against the prefusion F protein conformation are considered more protective, since they neutralize the protein and associated RSV virion before the virus fuses with the host, leaving the viral machinery incapable of making progeny virions inside the cell. First author Velasco Cimica, with lead scientist Jose Galarza, hypothesized that the F protein conformation, as well as its presentation in a lipid membrane, would affect the protective efficacy of an RSV vaccine.
To test this, Cimica and colleagues generated virus-like particles (VLPs) – which look like the virus to the immune system (see image, right) but don’t contain the viral genome, and therefore cant make progeny virus – that had prefusion or postfusion F proteins, or that contained a combination of the two. Mice immunized with one of these three VLP preps were then challenged with RSV. All animals were protected against disease – with no detectable viral titers after 4 or 7 days of infection, demonstrating vaccine efficacy – but the animals treated with the prefusion F-VLP vaccine had the highest concentration of neutralizing antibodies.
A deeper investigation into the immune response revealed a strong IFNg and Th1 cytokine response from all three VLP vaccines, without coordinate Th2 cytokines (IL-4, IL-10, IL-17), which are associated with exacerbated disease. RSV pneumonia has a large influx of immune cells recruited from chemokines, which were slightly elevated in the prefusion-treated animals but were close to background in both postfusion F and combination-treated animals. Lung inflammation is a fine line for the immune system to toe; the body must fight infection without damaging tissue architecture to maintain function. The researchers looked at lung structure to measure possible negative side effects of an overactive immune system.
Fortunately, the low inflammatory levels were reflected in animal lung pathology. Mice were unimmunized or immunized with the combination VLP or a formalin-inactivated virus before viral challenge. The unimmunized mice developed slight inflammation, as is typical for RSV disease (see placebo photo, left). The inactivated virus-immunized mice experienced massive inflammatory cell influx, blocking a majority of the airways. But the VLP-immunized mice had no inflammation, demonstrating the VLP vaccine is both safe and effective in mice.
With no currently licensed vaccine to prevent RSV infection, the best preventative medication is a monthly injection of protective antibodies (also generated against the F protein). A safe and effective vaccine could prevent the over 50,000 hospitalizations in the United States and hundreds of thousands of deaths each year worldwide due to RSV infection. A VLP-based approach, like that described here, may be the best way to achieve a safe, effective vaccine.
-- Julie Wolf
Photo credits: All figures taken from CVI paper discussed