A first step towards a universal vaccine against pneumonia, meningitis

There is a bacterium called Streptococcus pneumoniae. It comes in at least a hundred different forms, or serotypes, and lives in the tissue lining our nose and throat. S. pneumoniae is normally harmless. But when your body’s immune system becomes weaker, for example when you have a viral fever, these bacteria may invade your lungs and cause pneumonia, your brain and spinal cord to cause meningitis, and your bloodstream to cause sepsis.

These diseases are called pneumococcal diseases, and fortunately, they can be prevented by vaccines. Each of these vaccines contains a unique sugary substance called a capsular polysaccharide, aimed at each serotype of S. pneumoniae. That is, they offer protection specific to each serotype.

And the current crop of pneumococcal vaccines protect against only a subset of the 100-odd serotypes. To increase coverage, scientists need to include additional serotype-specific capsular polysaccharides in the vaccine. And covering all the serotypes in a single shot would be extremely challenging, not to mention extremely expensive as well.

Recently, a team of British scientists reported an important first step in this direction. They did two things: first, they switched the polysaccharide with proteins and, second, they adopted an approach called reverse vaccinology.

Basically, two kinds of pneumococcal vaccines are available today. One is a mix of purified capsular polysaccharides from multiple serotypes. Pneumovax 23 is an example. It does not work well in infants and offers short-lived protection.

To help boost the effects as well as the durability of the immune response, scientists have linked the polysaccharides to a carrier protein. Such vaccines are known as pneumococcal conjugate vaccines (PCVs). Typical examples include PCV10 and PCV14; the numerals denote the number of serotypes included.

When these vaccines target and eliminate some serotypes of S. pneumoniae, it also opens the door for other serotypes to mount an infection. These non-vaccine serotypes also face less biological competition for space and resources, so they multiply and eventually replace the vaccine-targeted serotypes, rendering the vaccines obsolete.

Second, many non-vaccine serotypes either possess antibiotic resistance genes or can acquire them from their resistant counterparts. This leads to the rise of both vaccine- and antibiotic-resistant serotypes.

Thus, scientists are looking for a universal pneumococcal vaccine that can target all serotypes and prevent these outcomes, which keep the threat of pneumonia, meningitis, and other pneumococcal diseases alive in the population.

Reverse vaccinology starts from the germ’s genome to identify proteins that can be included in vaccines. Scientists demonstrated an example of this in the recent COVID-19 pandemic: once the virus’s genome was sequenced in early 2020, scientists around the world could analyse it and zero in on the spike-protein gene to make COVID-19 vaccines. The approach completely bypassed the need to culture the germs in large bioreactors and purify molecular components from them to make the vaccine.

The S. pneumoniae genome encodes more than 2,000 genes. Of them, around 1,300 are common across serotypes. The genomic data of more than 20,000 S. pneumoniae isolates across nearly a hundred serotypes are also available in the public domain. The scientists deployed extensive computational analysis using an arsenal of bioinformatic tools to analyse these sequences.

They reasoned that the best candidate genes for creating their universal vaccine would need to encode for proteins with three attributes: (i) it must be located on the surface so that the immune system can easily access it; (ii) it must have low or no similarity to human proteins, so that the immune system does not attack the body’s tissue, and (iii) it must be capable of eliciting a robust and durable anti-pneumococcal immunity.

The team shortlisted some candidates and further whittled the list down based on their predicted shapes and stability. From this, the team picked three candidate genes. They were: zinc metalloprotease B (Z), pneumococcal adherence virulence factor A (P), and a protein which the scientists designated YfhO-like (Y) due to its similarity to another bacterial protein.

The team produced proteins Z, P, and Y in the laboratory and made an experimental vaccine by mixing them together. They also added two non-protein immune response boosters: a small piece of synthetic DNA called CpG and a sugary polymer called chitosan. They named this formulation ZPY-CpG-Ch.

To test whether the vaccine could elicit protective anti-pneumococcal antibodies, the scientists vaccinated laboratory mice. After some time, they exposed the mice to a lethal dose of S. pneumoniae serotype 1, which is known to be hypervirulent. Compared to unvaccinated mice, all of which succumbed to the lethal dose, vaccinated mice showed 80-100% survival. Importantly, the scientists found that the level of protection offered by ZPY-CpG-Ch was comparable to that of PCV13.

The team also found that antibodies from the mice vaccinated with ZPY-CpG-Ch could help kill S. pneumoniae bacteria in a test tube. When injected into unvaccinated mice, the antibodies could also protect them against a lethal dose of serotype 1.

Third, ZPY-CpG-Ch fully protected vaccinated mice exposed to lethal doses of two non-vaccine serotypes, 11A and 33F. It also offered 50% protection against a third non-vaccine serotype, called serotype 8.

In all mouse experiments, measures of the vaccine’s protective effect based on the bacterial load in lungs and blood mirrored the rodents’ survival rates. However, the ZPY-CpG-Ch vaccine did not reduce the load of pneumococcal bacteria in the upper respiratory passages of vaccinated mice. That is, despite being protected, vaccinated mice have the ability to still spread the infection to uninfected mice.

Finally, the team also reported that vaccinating mice with ZPY-CpG-Ch stimulated a subset of immune cells that are implicated in pneumococcal immunity.

The results from this work are too preliminary for ZPY-CpG-Ch to be a universal pneumococcal vaccine. It has also been tested against a very small subset of serotypes, four to be precise. Vaccine data from laboratory mice also may not truly reflect the human situation.

Nevertheless, this work represents a baby step towards the worthy goal of developing a universal pneumococcal vaccine.

S. Swaminathan is a retired professor of biology at BITS-Pilani, Hyderabad, and a former scientist at ICGEB, New Delhi.