Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole‐cell inactivated pneumococcal vaccine

Abstract

Existing capsular polysaccharide-based vaccines against pneumococcal disease are highly effective against vaccine-included serotypes, but they are unable to combat serotype replacement. We have developed a novel pneumococcal vaccine that confers serotype-independent protection, and could therefore constitute a "universal" vaccine formulation. This preparation is comprised of whole un-encapsulated pneumococci inactivated with gamma irradiation (c-PN), and we have previously reported induction of cross-reactive immunity after nonadjuvanted intranasal vaccination. To further enhance vaccine immunogenicity and safety, we modified the pneumococcal vaccine strain to induce a stressed state during growth. Specifically, the substrate binding component of the psaBCA operon for manganese import was mutated to create a pneumococcal surface antigen A (psaA) defective vaccine strain. psaA mutation severely attenuated the growth of the vaccine strain in vitro without negatively affecting pneumococcal morphology, thereby enhancing vaccine safety. In addition, antibodies raised against vaccine preparations based on the modified strain [c-PN(DPsaA)] showed more diversified reactivity to wild-type pneumococcal challenge strains compared to those induced by the original formulation. The modified vaccine also induced comparable protective T H 17 responses in the lung, and conferred greater protection against lethal heterologous pneumococcal challenge. Overall, the current study demonstrates successful refinement of a serotype-independent pneumococcal vaccine candidate to enhance safety and immunogenicity.

In vivo dual RNA-seq reveals that neutrophil recruitment underlies differential tissue tropism of Streptococcus pneumoniae

“…Mice were euthanized by CO 2 asphyxiation at 6 h, then lungs were finely macerated in 1 mL prewarmed digestion medium (DMEM + 5% FCS, 10 mM HEPES, 2.5 mM CaCl 2 , 0.2 U mL −1 penicillin/gentamicin, 1 mg mL −1 collagenase IA, 30 U mL −1 DNase) and incubated at 37°C for 1 h with mixing every 20 min. Single cells were then prepared for acquisition on a BD LSRFortessa X20 flow cytometer as previously described 35 . The single cell suspensions were stained using antibodies against surface markers listed in Supplementary Table 4, allowing the enumeration of a number of immune cell subsets, as previously described 12 .…”

Panel 3: Genomics, precision medicine and targeted therapies

“…A genetically engineered unencapsulated killed strain of Spn that elicits IL-17A production is in clinical trials [164,165]. Additional preclinical WCVs using different engineered strains and different routes of immunization (intraperitoneal or intranasal) are being studied [166,167].…”

Protective Effect of Nasal Colonisation with ∆cps/piaA and ∆cps/proABCStreptococcus pneumoniae Strains against Recolonisation and Invasive Infection

“…A high proportion of adults have effective naturally acquired immunity against S. pneumoniae [11,12], which extensive human and mouse data suggest develops in response to natural S. pneumoniae colonisation of the nasopharynx. Colonisation induces antibody and CD4+ Th17 responses to protein antigens and antibody to capsular antigen, preventing recolonisation of the nasopharynx, pneumonia and sepsis [13][14][15][16][17][18][19][20][21][22][23][24]. These responses are likely to contribute to the decrease in rates of S. pneumoniae in older children and adults compared to infants [12].…”