A Cross-Reactive Protein Vaccine Combined with PCV-13 Prevents Streptococcus pneumoniae- and Haemophilus influenzae-Mediated Acute Otitis Media

Abstract

Acute otitis media is one of the most common childhood infections worldwide. Currently licensed vaccines against the common otopathogen Streptococcus pneumoniae target the bacterial capsular polysaccharide and confer no protection against nonencapsulated strains or capsular types outside vaccine coverage. Mucosal infections such as acute otitis media remain prevalent, even those caused by vaccine-covered serotypes. Here, we report that a protein-based vaccine, a fusion construct of epitopes of CbpA to pneumolysin toxoid, confers effective protection against pneumococcal acute otitis media for non-PCV-13 serotypes and enhances protection for PCV-13 serotypes when coadministered with PCV-13. Having cross-reactive epitopes, the fusion protein also induces potent antibody responses against nontypeable Haemophilus influenzae and S. pneumoniae, engendering protection against acute otitis media caused by emerging unencapsulated otopathogens. These data suggest that augmenting capsule-based vaccination with conserved, cross-reactive protein-based vaccines broadens and enhances protection against acute otitis media.

Multi-Valent Protein Hybrid Pneumococcal Vaccines: A Strategy for the Next Generation of Vaccines

“…Promising results in models against pneumonia and upper respiratory infection, known deficits of PCVs, resulted in enthusiasm for assessing safety and efficacy in human clinical trials. In several Phase I randomized clinical trials, this triad was uniformly safe and antigenic [ 94 , 110 , 111 , 112 , 113 , 114 , 115 ]. Unfortunately, analysis for protection against carriage or otitis media showed no benefit [ 116 , 117 , 118 ].…”

“…YLN (YPT-L460D-NEEK) is a single hybrid protein created by fusing the DNA sequences for two domains of cbpA (YPT, pIgR binding domain and NEEK, Laminin receptor binding domain) to a gene for a toxoid of pneumolysin (L460D) ( Figure 3 B) [ 63 , 92 , 108 , 109 , 111 , 112 , 113 , 114 , 115 ]. The L460D substitution disrupts the cholesterol recognition motif, thereby strongly reducing cytotoxicity [ 119 ].…”

“…In a sepsis mouse model, the mortality of mice vaccinated with YLN was significantly decreased against several pneumococcal strains and this protective phenotype extended to organ specific bacterial burdens as well [ 63 ]. Unlike with PCV, the YLN vaccine was demonstrated to be protective against otitis media caused by a non-encapsulated strain [ 113 ]. Antibodies against CbpA have been demonstrated to also recognize the LR binding proteins of meningococcus and H. influenzae [ 94 ] and thus provide cross protection for meningitis and otitis for three frequent pathogens in these sites [ 88 , 92 , 120 ].…”

Perspective of a Pediatrician: Shared Pathogenesis of the Three Most Successful Pathogens of Children

“…Cross-reactivity between the meningeal pathogens of the ligands for laminin receptor-mediated translocation is highlighted by the observation that induction of antibody by vaccination with CbpA conveys protection not only against pneumococcal infection but also against Haemophilus sepsis and otitis media and meningococcal meningitis in mouse models ( Mann et al., 2014 ; Rowe et al., 2019 ). A CbpA-based vaccine is effective in preventing cardiac lesions based on blocking the shared CbpA/laminin receptor mechanism ( Mann et al., 2014 ).…”

Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

“…Similarly, shared motifs for the binding of bacteria to laminin receptors indicate that antibodies to a single bacterial protein can be broadly cross-protective against pathogens that use the same invasive strategy. This has been demonstrated using immunization with the pneumococcal laminin receptor binding protein, choline binding protein A (CbpA/PspC), resulting in protection against pneumococcal, Haemophilus, and meningococcal diseases [19][20][21][22]. Should this antigen strategy be developed into a vaccine, it is expected that the serum would need to be tested not just for high titer antibodies, but also for a high level of antibodies active in a functional assay reflecting CbpA binding to laminin receptor in vitro.…”