2023-11-01 08:00:00
»RSV has previously accounted for a large proportion of illnesses and deaths around the world. I think that will change dramatically,” says Louis Bont, an infectious diseases pediatrician at the University Medical Center Utrecht in the Netherlands. However, he cautions that this positive development is unlikely to occur equally everywhere: costs and infrastructure problems will certainly delay some populations’ access to the medicines in low- and middle-income countries. Even in wealthier parts of the world, the question arises as to how different prevention strategies can be used most safely and effectively.
The first attempt to develop a vaccine against RSV began clinical testing in the 1960s. That was less than a decade after scientists first isolated the pathogen from young children with severe pneumonia. However, the approach proved to be a disaster; it even led to the symptoms of the disease worsening. “This has hindered efforts to find a successful vaccine for decades,” says Varga (see “Friendly Fire”). In the past ten years, the development of RSV vaccines has accelerated again. Among other things, experts identified a virus component that causes a strong immune reaction, which in turn can neutralize the infection and prevent it from becoming severe.
Friendly Fire
The ideal effect of a vaccine – which is rarely achieved in practice – is 100 percent protection of the recipient against all future encounters with the pathogen. The success of a vaccine can also be measured by whether it prevents serious diseases or reduces their transmission. However, the first vaccine against respiratory syncytial virus (RSV) did not even cross this threshold. Four clinical trials in the late 1960s were an example of a worst-case scenario – the vaccination caused a significantly more severe course of the disease: In a study with 71 infants, 80 percent of vaccinated children who became infected with RSV were subsequently hospitalized, compared to just five percent of the control group. Two of the vaccinated children who were treated in intensive care ultimately died from the infection.
This alarming result was surprising for several reasons; among other things, because the vaccine itself was unremarkable. The RSV particles were inactivated by treating them with formalin – an agent that chemically stabilizes proteins so that they can no longer carry out their intended biological function. This was combined with an immune-stimulating substance made from aluminum salts called alum. This approach was standard in the 1960s. Both formalin inactivation and alum adjuvants continue to be used for some modern vaccines, according to Steven Varga, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. For example, hepatitis B and pneumococcal vaccines use alum, and inactivated polio vaccines are made from virus particles deactivated in formalin.
Only after decades of investigations and debates were experts able to clarify the factors that led to this negative scenario. “It was a coincidence of several events that led to the vaccine-aggravated illness in the children,” explains Varga. One of them: Through the formalin treatment, the virus particles acquired a structure that stimulates the production of antibodies in the body, which bind quite well to the viral proteins; however, they are unable to neutralize RSV infection. In fact, some studies suggest that they can accumulate as immune complexes in the lungs and trigger a harmful inflammatory response.
At the same time, the inactivated virus apparently impairs the formation of killer T cells, which normally destroy virus-infected cells in future encounters. This left a crucial gap in the antiviral immune system. Instead, the vaccine triggered a strong response from a subset of T helper cells, which recruited a host of other immune cells during infection, which in turn could trigger a strong and damaging inflammatory response in the lungs.
This is not a phenomenon unique to RSV – similar problems occurred with a formalin-inactivated measles vaccine in the same decade. However, the inactivation of formalin does not appear to be a problem with other vaccine preparations. Varga notes that both measles and RSV belong to the paramyxovirus family. “I think it’s a common problem for this particular group of viruses,” he says.
Fortunately, subsequent cases of illness caused by the vaccine have been extremely rare. And according to Louis Bont, an infectious diseases pediatrician at the University Medical Center Utrecht in the Netherlands, vaccine developers are now much better able to intercept such effects before they occur in humans. “In the 1960s we thought we could develop a vaccine against everything overnight,” explains Bont. “Preclinical and early clinical development is now much more regulated.”
RSV relies on a surface molecule known as a fusion protein (F) to bind to and invade host cells. Virologists quickly realized that this protein is a promising target for an antibody-mediated immune attack. However, it comes in different variants. F alternates smoothly between a compact “pre-” and an extended “post-fusion” structure. The prefusion form, which makes it easier for the virus to penetrate the cell membrane, can be easily neutralized by binding antibodies. For this reason, they are an excellent target for vaccines.
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