Gene-based neonatal immune priming potentiates a mucosal adenoviral vaccine encoding mycobacterial Ag85B
Guixiang Dai1, Hamada F Rady1, Weitao Huang1
1Department of Microbiology, Immunology & Parasitology, LSUHSC-New Orleans, LA 70112, USA; The Louisiana Vaccine Center, LSUHSC-New Orleans, LA 70112, USA.
Insights
Neonatal DNA vaccination primes infants for enhanced protection against tuberculosis (TB). Early immunization followed by a later adenovirus boost significantly boosts immune responses and reduces bacterial load in mice.
Area of Science:
- Immunology
- Vaccinology
- Microbiology
Background:
- Tuberculosis (TB) is a global health threat, with infants being highly susceptible.
- Current BCG vaccines offer limited and variable protection, especially in adults and immunocompromised individuals.
- A safe, early-life vaccine that enhances future booster responses is needed.
Purpose of the Study:
- To evaluate gene-based vaccine vectors expressing Ag85B for TB prevention.
- To assess heterologous prime-boost strategies, particularly neonatal DNA priming followed by mucosal boosting.
- To determine if early immunization can prime for improved vaccine efficacy.
Main Methods:
- Developed DNA and recombinant adenovirus vaccine vectors encoding Mycobacterium tuberculosis Ag85B.
- Administered DNA vaccines intradermally to neonatal mice.
- Administered adenovirus vectors intranasally to six-week-old mice.
- Utilized a heterologous prime-boost strategy (DNA prime, adenovirus boost).
- Assessed immunogenicity (T cell responses) and protective efficacy against Mtb H37Rv challenge.
Main Results:
- Neonatal DNA vaccination alone showed limited protection.
- Adenovirus boosting alone induced moderate responses and poor protection.
- Neonatal DNA priming followed by intranasal adenovirus boosting generated robust Ag85B-specific CD4+ and CD8+ T cell responses.
- This prime-boost strategy significantly reduced bacterial burden in the lungs post-challenge.
- Responders exhibited enhanced capacity to secrete antimicrobial factors.
Conclusions:
- Early-life immunization with gene-based vaccines can prime the immune system.
- Heterologous prime-boost vaccination strategies enhance vaccine efficacy against TB.
- Neonatal DNA priming potentiates subsequent mucosal boosting with adenovirus vectors.
- This approach holds promise for developing effective early-life TB vaccines.
Abstract:
Tuberculosis remains a major public health hazard worldwide, with neonates and young infants potentially more susceptible to infection than adults. BCG, the only vaccine currently available, provides some protection against tuberculous meningitis in children but variable efficacy in adults, and is not safe to use in immune compromised individuals. A safe and effective vaccine that could be given early in life, and that could also potentiate subsequent booster immunization, would represent a significant advance. To test this proposition, we have generated gene-based vaccine vectors expressing Ag85B from Mycobacterium tuberculosis (Mtb) and designed experiments to test their immunogenicity and protective efficacy particularly when given in heterologous prime-boost combination, with the initial DNA vaccine component given soon after birth. Intradermal delivery of DNA vaccines elicited Th1-based immune responses against Ag85B in neonatal mice but did not protect them from subsequent aerosol challenge with virulent Mtb H37Rv. Recombinant adenovirus vectors encoding Ag85B, given via the intranasal route at six weeks of age, generated moderate immune responses and were poorly protective. However, neonatal DNA priming following by mucosal boosting with recombinant adenovirus generated strong immune responses, as evidenced by strong Ag85B-specific CD4+ and CD8+ T cell responses, both in the lung-associated lymph nodes and the spleen, by the quality of these responding cells (assessed by their capacity to secrete multiple antimicrobial factors), and by improved protection, as indicated by reduced bacterial burden in the lungs following pulmonary TB challenge. These results suggest that neonatal immunization with gene-based vaccines may create a favorable immunological environment that potentiates the pulmonary mucosal boosting effects of a subsequent heterologous vector vaccine encoding the same antigen. Our data indicate that immunization early in life with mycobacterial antigens in an appropriate vaccine setting can prime for protective immunity against Mtb.
