Lactococcus lactis as an adjuvant and delivery vehicle of antigens against pneumococcal respiratory infections

Abstract

Most studies of Lactococcus lactis as delivery vehicles of pneumococcal antigens are

focused on the effectiveness of mucosal recombinant vaccines against Streptococcus

pneumoniae in animal models. At present, there are three types of pneumococcal

vaccines: capsular polysaccharide pneumococcal vaccines (PPV), protein-

polysaccharide conjugate pneumococcal vaccines (PCV) and protein-based

pneumococcal vaccines (PBPV). Only PPV and PCV have been licensed. These

vaccines, however, do not represent a definitive solution. Novel, safe and inexpensive

vaccines are necessary, especially in developing countries. Probiotic microorganisms

such as lactic acid bacteria (LAB) are an interesting alternative for their use as vehicles

in pneumococcal vaccines due to their GRAS (Generally Recognized As Safe) status.

Thus, the adjuvanticity of Lactococcus lactis by itself represents added value over the

use of other bacteria, a question dealt with in this review. In addition, the expression of

different pneumococcal antigens as well as the use of oral and nasal mucosal routes of

administration of lactococcal vaccines is considered. The advantages of nasal live

vaccines are evident; nonetheless, oral vaccines can be a good alternative when the

adequate dose is used. Another point addressed here is the use of live versus inactivated

vaccines. In this sense, few researches have focused on inactivated strains to be used as

vaccines against pneumoccoccus. The immunogenicity of live vaccines is better than the

one afforded by inactivated ones; however, the probiotic-inactivated vaccine

combination has improved this matter considerably. The progress made so far in the

protective immune response induced by recombinant vaccines, the successful trials in

animal models and the safety considerations of their application in humans suggest that

the use of recombinant vaccines represents a good short-term option in the control of

pneumococcal diseases.

Figures and Tables

Figure 1 Innate immune response in lung. Alveolar macrophages constitute the first line of phagocytic defense against infectious agents and play a prominent role in lung immunity by initiating inflammation and immune responses. In the event that invading pathogens are too virulent or represent too large a load to be contained by macrophages alone, alveolar macrophages are capable of generating mediators that orchestrate the recruitment of large numbers of neutrophils from the pulmonary vasculature into the alveolar space. These neutrophils provide auxiliary phagocytic capacities that play a critical role in host defense against pathogens.

Figure 2 Antigen uptake and migratory pattern induction in the airways. The production of specific IgA in the respiratory tract during an infectious process is very important because it prevents colonization of mucosal sites and subsequent spreading into the systemic circulation.

Figure 3 Antigen uptake and migratory pattern for immune induction in deep lung. IgG production plays an important role in the protection against pathogens that reach the alveolar space. Opsonizing IgG antibodies are important for complement fixation and for improvement in the efficiency of macrophages killing. At the systemic level, immune activation also induces production of antibodies responsible for preventing the passage of pathogens to the blood.

Figure 4 Schematic representation of the nisin-controlled gene expression (NICE) system (40) used to express the recombinant PppA pneumococcal protein in L. lactis. L. lactis NZ9000 cells containing the signal transduction genes nisK and nisR in their chromosome were transformed with a plasmid carrying the pppA gene under the control of the inducible promoter P_nisA. Expression of the PppA recombinant protein was induced by the addition of sub-inhibitory amounts of the nisin and its insertion in the cell wall was mediated by the secretion (sec) and cell wall (CW) anchoring signals.

Table 1 Lactic acid bacteria as vaccine vehicles against S. pneumoniae