Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles.

UNLABELLED: At least 15 high-risk human papillomaviruses (HPVs) are linked to anogenital preneoplastic lesions and cancer. Currently, there are three licensed prophylactic HPV vaccines based on virus-like particles (VLPs) of the L1 major capsid protein from HPV-2, -4, or -9, including the AS04-adjuvanted HPV-16/18 L1 vaccine. The L2 minor capsid protein contains HPV-neutralizing epitopes that are well conserved across numerous high-risk HPVs. Therefore, the objective of our study was to assess the capacity to broaden vaccine-mediated protection using AS04-adjuvanted vaccines based on VLP chimeras of L1 with one or two L2 epitopes. Several chimeric VLPs were constructed by inserting L2 epitopes within the DE loop and/or C terminus of L1. Based on the shape, yield, size, and immunogenicity, one of seven chimeras was selected for further evaluation in mouse and rabbit challenge models. The chimeric VLP consisted of HPV-18 L1 with insertions of HPV-33 L2 (amino acid residues 17 to 36; L1 DE loop) and HPV-58 L2 (amino acid residues 56 to 75; L1 C terminus). This chimeric L1/L2 VLP vaccine induced persistent immune responses and protected against all of the different HPVs evaluated (HPV-6, -11, -16, -31, -35, -39, -45, -58, and -59 as pseudovirions or quasivirions) in both mouse and rabbit challenge models. The degree and breadth of protection in the rabbit were further enhanced when the chimeric L1/L2 VLP was formulated with the L1 VLPs from the HPV-16/18 L1 vaccine. Therefore, the novel HPV-18 L1/L2 chimeric VLP (alone or in combination with HPV-16 and HPV-18 L1 VLPs) formulated with AS04 has the potential to provide broad protective efficacy in human subjects. IMPORTANCE: From evaluations in human papillomavirus (HPV) protection models in rabbits and mice, our study has identified a prophylactic vaccine with the potential to target a wide range of HPVs linked to anogenital cancer. The three currently licensed vaccines contain virus-like particles (VLPs) of the L1 major capsid protein from two, four, or nine different HPVs. Rather than increasing the diversity of L1 VLPs, this vaccine contains VLPs based on a recombinant chimera of two highly conserved neutralizing epitopes from the L2 capsid protein inserted into L1. Our study demonstrated that the chimeric L1/L2 VLP is an effective vehicle for displaying two different L2 epitopes and can be used in a quantity equivalent to what is used in the licensed vaccines. Hence, using the chimeric L1/L2 VLP may be a more cost-effective approach for vaccine formulation than adding different VLPs for each HPV.

Pneumococcal serotype 3 otitis media, limited effect of polysaccharide conjugate immunisation and strain characteristics.

BACKGROUND: In contrast to the other vaccine serotypes, no protection could be demonstrated in the POET study against serotype 3 acute otitis media (AOM) following primary and booster vaccination with a multi-valent pneumococcal conjugate vaccine. METHODS: AOM efficacy and immunogenicity data were reviewed. Pheno- and genotypic characteristics of different serotype 3 strains including efficacy study AOM isolates were evaluated. RESULTS: Evaluation of vaccine efficacy before and after booster vaccination indicated that lack of efficacy against serotype 3 pneumococci might have been due to declined protection following the booster dose. However, although atypical immunogenicity was observed for serotype 3 in the second year of life, the capacity to respond to serotype 3 plain polysaccharide was not impaired. All but one of the serotype 3 strains examined had abundant polysaccharide capsules. Comparison of serotype 3 capsular polysaccharide biosynthesis gene sequences found no relevant differences between any of the serotype 3 strains, but mRNA transcript levels were lower for the less densely encapsulated strain. CONCLUSION: Lack of clinical efficacy against serotype 3 AOM following pneumococcal conjugate vaccination may be due to an impaired induction of immune memory. A possible alternative explanation may lie with the atypically abundant expression of capsular polysaccharide which could make serotype 3 strains less susceptible to anti-polysaccharide antibody defence mechanisms in the middle ear. The occurrence of acapsular forms during biofilm growth may also play a role. Clinical impact against otitis media, of vaccines containing pneumococcal serotype 3 components, remains unclear until further investigations have demonstrated the value.