ReviewLive attenuated vaccines for invasive Salmonella infections
Introduction
The first vaccines against typhoid fever consisting of heat-inactivated typhoid bacilli preserved in phenol administered parenterally, were developed in the late 19th century [1]. Experiences with implementation of typhoid vaccines in the British and US military in the early 20th century and subsequent large-scale controlled field trials sponsored by the World Health Organization documented that the inactivated whole cell vaccines were efficacious but were highly reactogenic [1]. Whole-cell vaccines against Salmonella enterica serovars Paratyphi A and B were also developed in the early 20th century and used by the U.S. military as a trivalent “TAB” vaccine against enteric fever [2]. However, these whole-cell vaccines lost favor due to their propensity to produce high fever, severe headache and malaise and gave way to the development of better tolerated Salmonella vaccines using other approaches such as parenteral polysaccharide and polysaccharide-protein conjugate vaccines and live attenuated oral vaccines. There are currently three types of licensed Salmonella vaccines: the live attenuated vaccine Ty21a marketed as Vivotif® (PaxVax Corporation); unconjugated Vi polysaccharide vaccine commercialized as Typhim Vi® (Sanofi Pasteur), Typherix® (GSK) and Typbar Vi® (Bharat Biotech), amongst others; and Vi polysaccharide conjugated to tetanus toxoid (Typbar TCV®, Bharat Biotech and Peda Typh™, Biomed).
Currently, licensed vaccines exist against no Salmonella serovars other than Salmonella Typhi (although Salmonella Typhi vaccine strain Ty21a confers moderate cross protection against Salmonella Paratyphi B as well as Salmonella Typhi) [3]. There is growing recognition that other invasive Salmonella serovars also cause a notable disease burden [4]. Salmonella Paratyphi A is emerging as a pathogen in Asia [5]; the non-typhoidal Salmonella serovars Salmonella Typhimurium and Salmonella Enteritidis cause invasive disease throughout sub-Saharan Africa [6], and Salmonella Group C serovars such as Salmonella Choleraesuis are associated with invasive disease in certain countries such as Taiwan [7]. As such, a multivalent vaccine that targets the following serovars is needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella).
At the Center for Vaccine Development, University of Maryland School of Medicine, we have developed and evaluated a variety of Salmonella live attenuated vaccines. There are several advantages of live oral attenuated vaccines over other vaccine formulations: (1) they can induce local immune responses at mucosal surfaces; (2) they are economical to produce; (3) they induce Salmonella-specific B and T cell immunity; (4) they are practical to administer to a large population; and (5) they do not generate hazardous waste (e.g., needles and syringes) that needs to be discarded appropriately [8], [9]. However, there are several limitations to live attenuated vaccines. First, one needs to balance immunity and reactogenicity, particularly if the vaccine is to be used as a live vaccine vector [10]. The vaccine may also need to be formulated differently for infants. For example, Ty21a at times has been available in both a sachet formulation for use in young children as well as enteric-coated capsules for use in older children and adults [11], [12], [13]. Finally, safety of live attenuated vaccines needs to be determined in immunocompromised subjects and also the very young prior to widespread use.
Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines.
Section snippets
Methods of attenuation
The first method used to mutate bacteria to create live attenuated vaccines was chemical mutagenesis. However, with the advent of molecular biology, live attenuated vaccines are now constructed by making focused site-directed mutations using genetic engineering.
Live attenuated vaccines against invasive Salmonella serovars
Since the majority of invasive Salmonella disease burden has traditionally been attributed to Salmonella Typhi, multiple typhoid vaccine candidates have been evaluated in clinical trials whereas vaccines against other Salmonella serovars have been neglected. Here, we describe some of the live attenuated invasive Salmonella vaccines that have been developed to date including vaccines that are currently in development (summarized in Table 1).
Conclusions
Despite the first Salmonella vaccines being developed over a century ago, invasive Salmonella disease is still a significant cause of mortality and morbidity worldwide. Due to improved surveillance efforts, there is a growing realization that in addition to preventing Salmonella Typhi, other invasive Salmonella serovars, particularly Salmonella Paratyphi A in Asia and Salmonella Typhimurium and Salmonella Enteritidis in sub-Saharan Africa should also be targeted. Live attenuated vaccines are an
Conflicts of interest
M.M.L. is the coinventor of the patent for attenuated Salmonella enterica serovar Typhi strains that constitutively express Vi capsular polysaccharide antigen. M.M.L. and S.M.T. are coinventors of a patent which describes multivalent Salmonella enterica serovar conjugate vaccines comprising conjugates of Salmonella Typhimurium, Salmonella Enteritidis, Salmonella Choleraesuis, Salmonella Typhi, Salmonella Paratyphi A and optionally Salmonella Paratyphi B.
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Address: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Tel.: +1 410 706 5328; fax: +1 410 706 6205.