Increased Protection against Pneumococcal Disease by Mucosal Administration of Conjugate Vaccine plus Interleukin-12

Abstract

Streptococcus pneumoniae is a common cause of respiratory tract infections, its main entry route being the nasal mucosa. The recent development of pneumococcal polysaccharide conjugate vaccines has led to a dramatic improvement in protection against invasive disease in infants and children, but these vaccines have been found to be only 50 to 60% protective against bacterial carriage. In this study, we investigated the efficacy of intranasal (i.n.) conjugate vaccine delivery using interleukin-12 (IL-12) as a mucosal adjuvant. Immunized mice treated with IL-12 demonstrated increased expression of lung and splenic gamma interferon and IL-10 mRNAs; high levels of antibody, particularly serum immunoglobulin G2a (IgG2a) and respiratory IgA; and significantly increased opsonic activity. After intraperitoneal challenge with type 3 pneumococci, there was 75% survival of i.n. vaccinated mice compared to 0% survival of unvaccinated mice. In addition, after i.n. challenge with type 14 pneumococci, vaccinated mice possessed fewer bacterial colonies in the upper respiratory tract than unvaccinated mice. However, no significant difference in type 14 carriage was observed between vaccinated and unvaccinated groups following intramuscular vaccination, the typical route of vaccination in humans. Using mice with a genetic disruption in IgA expression, it was found that pneumococcus-specific IgA played a significant role in the clearance of bacteria from the upper respiratory tract. We conclude that i.n vaccination in the presence of IL-12 is able to enhance systemic and mucosal immune responses to pneumococci and efficiently protect against both invasive infection and bacterial carriage.Streptococcus pneumoniae colonizes the human nasopharynx and is a common etiologic agent of respiratory tract infection. In addition, infection with the pneumococcus frequently results in bacteremia and sepsis because of its capacity to invade the bloodstream (19,30). Consequently, vaccination strategies against these pathogens, whose main entry route is the mucosal layer, need to involve both systemic and mucosal immune responses. The recently introduced pneumococcal conjugate vaccine, which is administered via the intramuscular (i.m.) route, effectively stimulates systemic immunity but is only partially effective against nasal colonization (10, 23). Administering the vaccine via the intranasal (i.n.) route could offer several advantages: (i) it would stimulate both mucosal and systemic immunity and thus offer effective protection against both invasive disease and nasal carriage, (ii) it would be easily administered, and (iii) it would be noninvasive and thus avoid the use of needles and the associated risks of transmitting hepatitis B and human immunodeficiency virus infection.Host protection against S. pneumoniae is mediated mainly by opsonin-dependent phagocytosis, and the opsonic activities of antibodies to pneumococcal capsular polysaccharides are believed to correlate with protection (1). It has been demonstrated (5, 7, 13, 32) that treatmen...

IL-12 as an adjuvant for the enhancement of protective humoral immunity

“…In addition, intranasal vaccination with PspA and IL-12 provided increased protection against nasopharyngeal carriage. The aforementioned results were obtained using a T-dependent pneumococcal protein antigen as the vaccine but, importantly, similar results have been observed using pneumococcal and meningococcal polysaccharide vaccines, given either as T-dependent conjugate vaccines, for example Prevnar ® , or as T-independent nonconjugated vaccines, such as Pneumovax ® [23][24][25]28,32]. In both cases, it was found that IL-12 treatment at the time of immunization induced significantly elevated levels of IgG2a and IgG3 anti-polysaccharide antibodies in serum, as well as IgA and IgG antibodies in the lung.…”

“…These include infections induced with influenza virus [22], Streptococcus pneumoniae [23][24][25], Francisella tularensis [26] and Yersinia pestis [Kumar D, Metzger DW, Unpublished Data]. We and others have repeatedly found that intranasal treatment of mice with IL-12 leads to increases in expression of both Th1-and Th2-associated antibodies in the serum [9][10][11][12][13][14] as well as in the lung [22][23][24][25][26][27]. In a typical experiment, mice are inoculated intranasally with vaccine only or vaccine plus IL-12.…”

An Important Role for Polymeric Ig Receptor-Mediated Transport of IgA in Protection against Streptococcus pneumoniae Nasopharyngeal Carriage

“…using IL-12 as an adjuvant essentially as described previously (14). In brief, mice were anesthetized and immunized i.n.…”

“…and parenteral immunization with polysaccharide conjugate vaccine, using IL-12 as a mucosal adjuvant as previously described (14). The role of SIgA in the defense against pneumococcal respiratory infection was also investigated using IgA gene-deficient (IgA Ϫ/Ϫ ) mice.…”

Serum and mucosal antibody responses to pneumococcal protein antigens in children:relationships with carriage status

“…Immunization via the nasal route can induce not only mucosal immunity but also antibody responses in serum [24][25][26]. Adenoids (nasopharyngeal tonsils) which are located in the anatomical area of pneumococcal carriage, are known to be important immune inductive sites for oropharyngeal immunity [27].…”