15 Feb 2023 How GPN Vaccines is outsmarting the pneumococcus
GPN Vaccines was initially established with the goal of creating a vaccine capable of protecting children and adults against all serotypes of Streptococcus pneumoniae (the pneumococcus), a deadly pathogen responsible for killing up to two million people worldwide each year. Such a vaccine represents the holy grail of pneumococcal vaccines, but due to serotype replacement, has eluded the best and brightest minds in the field. In this article, we explain how GPN Vaccines is tackling the problem in a different way.
What is serotype replacement?
The pneumococcus exists as at least 100 different serotypes, which are distinguished by capsular polysaccharides expressed on the cell surface. Each serotype is immunologically different and currently approved vaccines (e.g. polysaccharide conjugate vaccines or PCVs) target a specific subset of serotypes. While PCVs are highly effective against the serotypes they cover, their widespread use means that the serotypes they do not cover increase in prevalence due to a phenomenon known as serotype replacement. This results in PCVs becoming less effective over time.
As an example, the first PCV Prevnar® was approved in the year 2000 and was effective against seven serotypes that were causing the greatest disease burden in children in the United States at the time. By 2010, Prevnar 13® had been introduced because the original seven serotypes were no longer the predominant causes of disease in children, and six replacement serotypes were now dominating. However by 2018, the disease burden caused by Prevnar 13® serotypes had diminished considerably and there was now a worrying increase in disease caused by other serotypes. In response to this Prevnar 20® was launched in 2022, adding an additional seven serotypes to the vaccine formulation in what is ultimately becoming a futile attempt at extending the range of serotypes covered. As expected, serotypes not covered by Prevnar 20® are already causing serious disease in children and adults.
What is our approach to serotype replacement?
Overcoming the problem of serotype replacement requires a complete overhaul of the current pneumococcal vaccine strategy. As such, our future-proof approach has been to create immunity to all current and emerging serotypes through a whole-cell vaccine (called Gamma-PNTM) that lacks capsular polysaccharide and expresses surface proteins common to all serotypes. The vaccine strain also has additional mutations that ensure safety, optimise expression of key protein antigens, and impart enhanced stability during manufacture at scale.
We have shown in the laboratory that the functional opsonophagocytic immune responses elicited by Gamma-PN are as effective (and often induced at a higher level) than the responses elicited by PCV vaccines to PCV-included serotypes. More importantly, however, we have seen strong opsonophagocytic immune responses to serotypes not covered by any of the currently licensed pneumococcal vaccines or those in development.
To further investigate these findings, we recently launched a first-in-human clinical trial in Australia assessing the safety, tolerability and immunogenicity of Gamma-PN. This includes testing the vaccine’s ability to elicit human opsonophagocytic antibodies against a broad range of serotypes including those not covered by any current vaccines or vaccines in development. The clinical trial is expected to provide world-first evidence that Gamma-PN is capable of protecting against serotypes not covered by any existing pneumococcal vaccines.
What are the other benefits of Gamma-PN?
Current pneumococcal PCVs are becoming increasingly complex and expensive to manufacture, as the capsular polysaccharide from each serotype needs to be purified and individually conjugated to a carrier protein, usually diphtheria toxoid, in what is a time-consuming and complex process involving hundreds of manufacturing steps. Gamma-PN production only requires a small number of manufacturing steps and can be completed within a few weeks, making production highly cost-effective compared to the manufacture of PCVs.
Whole cell vaccines have been traditionally inactivated using chemical methods such as formalin and β-propiolactone, which are widely known to have a detrimental impact on antigen structure and subsequently vaccine immunogenicity. Gamma-PN is inactivated using gamma irradiation, a novel and safe approach which damages DNA whilst leaving delicate antigen structures intact.
Further, most vaccines require an adjuvant, which is a substance that enhances our immune response to an antigen, with aluminum often being used. The adjuvant can sometimes be responsible for the mild to moderate side-effects associated with vaccination. Surprisingly, we have found Gamma-PN performs better without an adjuvant and as a consequence, no adjuvant is added to our formulation.
GPN Vaccines will be at the World Vaccine Congress in Washington D.C. in April 2023 if you would like to connect with us.
This article was written by Peter Mills, Dr Lauren Giorgio and Professor James Paton; and illustrated by Carla Gallasch and Malachi Obst.
 Cleary, DW et al (2022) Changes in serotype prevalence of Streptococcus pneumoniae in Southampton, UK between 2006 and 2018. Scientific Reports 12: 13332
 David, SC et al (2022) A Nonadjuvanted Whole-Inactivated Pneumococcal Vaccine Induces Multiserotype Opsonophagocytic Responses Mediated by Noncapsule-Specific Antibodies. mBio 13(5)