Before the new crown vaccine, Pfizer's 13-valent pneumococcal vaccine was the world's "king of vaccines", with global sales of nearly 6 billion US dollars in 2018, far exceeding the second-place 9-valent HPV vaccine (3.15 billion US dollars).

No one wants to miss such a big market. While domestic companies are still rolling up the 13-valent pneumococcal vaccine (PCV13), Vaxcyte is rolling up the price type upgrade. VAX-24 is a vaccine covering 24 virus types, while VAX-31 has rolled up 31 types.

Of course, the 13-valent pneumococcal vaccine has brought epoch-making changes to the prevention of pneumonia. However, while the popularity of PCV13 has greatly increased, it has also brought new troubles: the replacement of virus types.

Since the introduction of PCV13, the incidence of diseases caused by the serotypes included in the vaccine has decreased. However, there is a phenomenon called serotype replacement, that is, after widespread vaccination, the incremental strains outside the serotype coverage will become the culprit of pneumonia.

The current US market has encountered this dilemma. According to data released in 2020, more than 71% of the incidence of IPD (pneumococcal pneumonia) in children and adults in 2017 was caused by strains other than the 13 strains covered by PCV13.

Obviously, we need a broader spectrum of PCVs to maintain protection against historical pathogenic strains while expanding coverage to address currently prevalent and emerging strains.

This is also the logic for continued iteration of pneumonia vaccines. Merck's PCV15 and Pfizer's PCV20 were both launched under this logic. Despite these advances, the coverage of these third-generation vaccines only addresses half of the prevalent diseases.

In this regard, Vaxcyte hopes to do more. VAX-24 and VAX-31 will increase coverage to approximately 63% and 95% of the diseases currently circulating in the adult population in the United States, respectively. This also supports the market's unlimited expectations for Vaxcyte.

"VAX-31's performance is shocking." After the release of Phase 1/2 data, an overseas analyst commented.

Indeed, whether it is immunogenicity or safety, it seems that VAX-31 is worth looking forward to.

In terms of immunogenicity, whether it is a high-dose or low-dose group, the combat effectiveness of VAX-31 is not weaker than Pfizer's 20-valent pneumococcal vaccine. VAX-31 achieves non-inferiority in all 20 serotypes, and some serotypes are even stronger. Specifically:

At high doses, all 20 serotypes meet the OPA response non-inferiority criteria, 18 of the 20 serotypes have a GMR greater than 1.0, and 7 serotypes achieve a statistically higher immune response.

At medium doses, all 20 serotypes meet the OPA response non-inferiority criteria, 13 of the 20 serotypes have a GMR greater than 1.0, and 5 serotypes achieve a statistically higher immune response.

At low doses, 18 of the 20 serotypes meet the OPA response non-inferiority criteria, 8 of the 20 serotypes have a GMR greater than 1.0, and three serotypes achieve a statistically higher immune response.

On average, the high-dose group of VAX-31 had a 25% higher immune response to shared serotypes, and the medium-dose group had a 10% higher immune response.

For all 11 incremental serotypes unique to VAX-31, all three doses met the superiority criteria. Therefore, in terms of effectiveness, VAX-31's performance is definitely beyond expectations.

Moreover, VAX-31 is relatively good in terms of safety and tolerability. According to the full six-month safety data, VAX-31 showed similar safety characteristics to PCV20 at all doses studied.

Given the positive data, Mizuho analysts said that VAX-31 has the potential to replace Pfizer's Prevnar 20, and may even replace Merck's 21-valent pneumococcal conjugate vaccine Capvaxive, which was just approved for marketing this year. Prevnar 20 can cover 52% of the virus types in this age group, while Capvaxive's target is 84%.

Considering that the market for pneumonia vaccines is expected to exceed tens of billions of dollars, the market is full of expectations for VAX-31. Although innovative drugs have encountered the strongest winter in history, Vaxcyte's stock price has risen by more than 320% since 2022, and its latest market value has exceeded US$12 billion, or about RMB 85.4 billion.

Although VAX-31 still has a long way to go before success. Vaxcyte expects to start Phase III clinical trials for all dose groups of VAX-31 by mid-2025 and complete them in 2026.

The high expectations of the market are understandable. If VAX-31 succeeds, it may bring extremely high competitive barriers to Vaxcyte. After all, a better pneumonia vaccine is not a simple price-stacking job.

The current pneumonia vaccine technology route has great limitations.

On the one hand, traditional coupling methods cannot control the coupling position of polysaccharides on protein carriers.

For example, the protein carrier used in all versions of Prevnar vaccine is CRM197, a diphtheria toxin that is rendered non-toxic by a single point mutation. The CRM197 protein contains 39 lysines, about 20% of which are adjacent to relevant T cell epitopes.

Conventional conjugation chemistry randomly attaches polysaccharides to numerous lysines on protein carriers. When lysine residues coexisting with T cell epitopes on polysaccharides are covalently bound to protein carriers, it blocks the presentation of T cell epitopes to the immune system, thereby preventing the induction of T cell responses.

Masking of these critical epitopes prevents the switch to a T cell-dependent immune response, offsetting the benefits of protein carriers.

On the other hand, there is a significant "carrier suppression" effect.

When B cell epitopes of protein carriers and antigens are presented to the immune system, it causes B cells to compete with each other for the respective immunogens to obtain unblocked T cell epitopes. This phenomenon reduces the immune response to polysaccharide antigens, leading to carrier suppression.

The result of carrier suppression is a reduction in the target immune response to disease-specific polysaccharides, which is exacerbated as the cumulative amount of protein carrier increases.

Therefore, a weakened immune response is an unavoidable reality as the valency increases. In a well-controlled phase 3 study in infants, PCV20 had lower IgG antibody responses against polysaccharides from all 13 common strains in each vaccine when compared to PCV13.

Moreover, the problem of carrier inhibition is exacerbated by the traditional conjugation chemistry used to make current pneumococcal conjugate vaccines, including PCV13, PCV15, and PCV20, which requires more CRM197 protein carrier than polysaccharide antigen to complete the conjugation reaction, as well as prolonged reactions and harsh conditions that can damage key epitopes on the polysaccharide antigen.

This results in higher ratios of protein carrier to polysaccharide antigen in their monovalent conjugates (average of about 1.1), as well as greater amounts of protein carrier accumulated in the final formulation compared to the amount of any given polysaccharide antigen.

For example, in the marketed PCV20 formulation, there are 51 micrograms of protein carrier CRM197 for each polysaccharide (4.4 micrograms for type 6B) of 2.2 micrograms. The amount of protein carrier in the vaccine far exceeds the polysaccharide antigen, which exacerbates the carrier inhibition effect discussed above.

For this reason, the road to covering more valence types is full of challenges. This is why analysts were shocked when they saw that VAX-31 showed non-inferiority to all serotypes targeted by PCV20. At the same time, they will give higher expectations.

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