Live attenuated vaccines for invasive Salmonella infections

Abstract

Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. 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.

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.