Search tips
Search criteria 


Logo of micLink to Publisher's site
Microbiology. 2013 January; 159(Pt 1): 1–11.
PMCID: PMC3542731

Pre-existing immunity against vaccine vectors – friend or foe?


Over the last century, the successful attenuation of multiple bacterial and viral pathogens has led to an effective, robust and safe form of vaccination. Recently, these vaccines have been evaluated as delivery vectors for heterologous antigens, as a means of simultaneous vaccination against two pathogens. The general consensus from published studies is that these vaccine vectors have the potential to be both safe and efficacious. However, some of the commonly employed vectors, for example Salmonella and adenovirus, often have pre-existing immune responses in the host and this has the potential to modify the subsequent immune response to a vectored antigen. This review examines the literature on this topic, and concludes that for bacterial vectors there can in fact, in some cases, be an enhancement in immunogenicity, typically humoral, while for viral vectors pre-existing immunity is a hindrance for subsequent induction of cell-mediated responses.


In the fields of medicine and veterinary medicine, there are numerous live, attenuated bacterial and viral vaccines in use today worldwide. The safety and efficacy of such vaccines is well established and allows further development as vector systems to deliver antigen originating from other pathogens. Various attenuated bacteria, including Escherichia coli, Vibrio cholerae, lactic acid bacteria (LAB), specifically Lactococcus lactis, Mycobacterium, Listeria, Shigella and Salmonella, have been tested for the targeted delivery of heterologous antigens of bacterial, viral and parasitic origin into a variety of animal hosts (Bahey-El-Din et al., 2010; Innocentin et al., 2009; Johnson et al., 2011; Tobias et al., 2008, 2010; Tobias & Svennerholm, 2012). Bacteria such as E. coli and lactic acid bacteria have recently gained favour, as E. coli is a commensal and lactic acid bacteria are present in most fermented food items and are therefore naturally present in the host. They are also a much safer option than traditional attenuated vaccines in children and immune-compromised people. As this review discusses the effects of pre-existing immune responses to attenuated vaccines, further discussion of LAB and E. coli as potential vectors will not be undertaken; however, the reader is directed to several interesting reviews (Bermúdez-Humarán et al., 2011; Wells & Mercenier, 2008).

Intracellular bacteria from the genera Mycobacterium (Guleria et al., 1996), Listeria (Gentschev et al., 2001), Shigella (Levine et al., 1997) and Salmonella (Dougan et al., 1987) are considered to be suitable candidates for the delivery of vaccine antigens due to their capability to induce robust T cell immune responses (Alderton et al., 1991; Lo et al., 1999; Mastroeni et al., 2001; Mittrücker & Kaufmann, 2000; Nauciel, 1990). Salmonella is one genus that has been well examined as a vector, building on the extensive research available on the micro-organism’s physiology and pathogenesis (Basso et al., 2000; Killeen & DiRita, 2000; Sirard et al., 1999; Ward et al., 1999). There exist several commercial vaccines that are used as anti-Salmonella vaccines in humans and animals (e.g. Ty21a for typhoid fever in humans, several Salmonella serovars against salmonellosis in chickens and other animals). The general strategy for vectoring heterologous antigen is depicted in Fig. 1. The first clinical trial of a recombinant, which was conducted over 20 years ago using an attenuated Salmonella as a delivery vector, led to the widespread testing of this bacterium as a mucosal delivery system for antigens from non-Salmonella pathogens (Dougan et al., 1987). These studies have demonstrated the utility of live bacteria to deliver expressed antigens and DNA vaccines to the host immune system (Atkins et al., 2006; Husseiny & Hensel, 2008; Jiang et al., 2004; Kirby et al., 2004). Since then several other intracellular bacterial vectors have been successfully tested for their capability to deliver a variety of antigens from various pathogens, as well as vaccination against cancer. One genus which has been widely tested as vector is Listeria. Listeria species are Gram-positive intracellular food-borne pathogens. The advantages of Listeria are that it can invade a variety of cells, including antigen presenting cells (APCs). After invading the host cell, Listeria resides inside the phagosome; however, it can escape the phagosome with the help of listeriolysin O (LLO; Hly) and reside in the cytoplasm of the cells, thereby efficiently presenting antigen to both CD8 and CD4 T cells (Cossart & Mengaud, 1989; Kaufmann, 1993; Pamer et al., 1997). Several studies have demonstrated the effectiveness and ease of using Listeria monocytogenes to deliver heterologous vaccine antigens and DNA vaccines (Brockstedt et al., 2004; Jensen et al., 1997; Johnson et al., 2011; Peters et al., 2003; Shen et al., 1995; Yin et al., 2011).

Fig. 1.
(a) General approach to using bacteria as vaccine vectors. In this case, the heterologous antigen is depicted as being expressed on the bacterial surface. (b) Salmonella secretion of heterologous antigen. STM-1 was engineered to secrete a haemolysin protein. ...

Similarly, various viral vectors have been successfully tested for their capability to deliver heterologous vaccine antigens, and this generally results in the induction of strong CTL immune responses. In the veterinary field, there are numerous viral vector vaccines that are currently licensed for use in livestock and domesticated animals. These recombinant vaccines are based on both DNA viruses (such as fowlpox virus-based vaccines which target avian influenza virus and fowlpox virus, or vaccinia virus-based vectors against the rabies virus in wildlife) and RNA viruses [such as Newcastle disease virus-based vaccines to be used in poultry or yellow fever virus (YFV)-based vaccines to be used in horses against West Nile virus] (Draper & Heeney, 2010). Based on the safety record in the veterinary field, many viruses have been studied for human use as a vector in vaccine development (Beukema et al., 2006; Esteban, 2009; Schirrmacher & Fournier, 2009; Stoyanov et al., 2010; Weli & Tryland, 2011). Amongst them, YFV (YF-17D strain) was the first to be licensed for use in humans, where the cDNAs encoding the envelope proteins of YFV were replaced with the corresponding genes of an attenuated Japanese encephalitis virus strain, SA14-14-2 (Appaiahgari & Vrati, 2010; Rollier et al., 2011). Poxviruses are also studied extensively as candidate vectors for human use, among which attenuated derivatives of vaccinia virus [such as modified vaccinia virus Ankara (MVA) and New York attenuated vaccinia virus NYVAC strains] are the most promising vectors (Esteban, 2009; Gómez et al., 2008; Rimmelzwaan & Sutter, 2009). They are ideal candidate vectors due to their large DNA-packing capacity and their thermal and genetic stability (Minke et al., 2004). The NYVAC vector has been shown to induce CD4+ T cell-dominant responses, and MVA induces both CD4+ and CD8+ T cell responses (Mooij et al., 2008). The adenovirus (Ad) vector is another of the most widely evaluated vectors to date to express heterologous antigens, due to ease of production, safety profile, genetic stability, the ease of DNA genome manipulation, and the ability to stimulate both innate and adaptive immune responses and induce both T and B cell responses (Alexander et al., 2012; Fitzgerald et al., 2003; Gabitzsch & Jones, 2011; Lasaro & Ertl, 2009; Vemula & Mittal, 2010; Weyer et al., 2009). They have been extensively examined as a delivery vector in several preclinical and clinical studies for infectious diseases such as anthrax, hepatitis B, human immunodeficiency virus (HIV)-1, influenza, measles, severe acute respiratory syndrome (SARS), malaria and tuberculosis (Chengalvala et al., 1994; Gao et al., 2006; Hashimoto et al., 2005; Hsu et al., 1992; Limbach & Richie, 2009; Radosevic et al., 2007; Shiver et al., 2002).

However, before vectored vaccines can be used in the human population they need to satisfy several important criteria. Safety is a major concern, as even a low level of toxicity is unacceptable (of course the minor discomfort that accompanies many vaccinations is normal). Secondly, a vaccine should be inexpensive, so that it can be administered to a large population at minimal cost, and this is particularly important in resource-poor countries (Killeen & DiRita, 2000). Similar constraints apply to veterinary vaccines, with cost often an even more important consideration. Finally, long-lasting cellular and (where appropriate) humoral immune responses to the vectored antigen must be induced following administration of these vaccines, preferably with a single dose (Atkins et al., 2006).

As some of the vectors in use will have been seen by the host immune system prior to vaccination, whether the presence of pre-existing immune responses is detrimental for the further development of a vector-based vaccine scheme, or can augment responses to the vectored antigen, needs to be considered in detail. This is the subject of this review. In discussing the possible effects on pre-existing immunity, the natural immunity to the vector needs to be considered. Therefore, considering a vector such as Salmonella, if a host has previously been infected there will exist robust B and T memory responses, and as such, when a vaccination is delivered, an anamnestic response to the Salmonella antigens will be induced (while the response to the vectored antigen will be a primary response). This will theoretically reduce the exposure of the heterologous antigen to the immune system, as the vector is rapidly cleared. Surprisingly, as will be seen in some of the examples given below, this can have results that differ depending on the magnitude of the response to the vectored antigen. Similarly, for virally vectored antigens, the existence of pre-existing immunity to the vector (particularly neutralizing antibody) will restrict delivery of the virus into cells, thereby effectively reducing the dose of the vectored antigen. Again, this might be expected to result in a reduction in the antigenicity of the vectored antigen.

Effects of prior immunological exposure to vectors – bacterial vectors

In the case of bacterial vectors, the effect of pre-existing immune responses has only been tested using Salmonella serovars and Listeria spp. Concern that prior immunological experience of the host with either the homologous Salmonella vector strain or a related strain might compromise its ability to deliver heterologous vaccine antigen was first raised in 1987 (Dougan et al., 1987). Bao and Clements subsequently reported experimental evidence of the consequences of prior exposure of animals to the vector strain (Bao & Clements, 1991). This work showed that both serum and mucosal antibody responses against the foreign antigen were in fact upregulated in animals with prior exposure to the vector strain. Whittle & Verma (1997) reported similar findings. Mice immunized via the intra-peritoneal route with a Salmonella dublin aroA mutant expressing heterologous antigen after being exposed to the same vector showed a higher immune response to the vectored antigen in comparison to mice without any immunological memory against the vector.

Subsequently, several studies have been conducted to examine the effect of pre-existing immunity in the host against Salmonella. These results are summarized in Table 1. The various reports are contradictory in their findings and seem to paint a rather confusing picture. Some studies concluded that pre-existing immunity against the Salmonella vector leads to stronger immune responses against the delivered antigen (Bao & Clements, 1991; Jespersgaard et al., 2001; Kohler et al., 2000a, b; Metzger et al., 2004; Saxena et al., 2009; Sevil Domènech et al., 2008; Whittle & Verma, 1997), with others considering pre-existing immunity to be a limiting factor in the long-term use of Salmonella as an efficient vector for antigen delivery (Attridge et al., 1997; Gahan et al., 2008; Roberts et al., 1999; Sevil Domènech et al., 2007; Vindurampulle & Attridge, 2003a, b).

Table 1.
Summary of published reports and their conclusions

A slight majority of the studies listed in Table 1 (10 versus eight) indicate the upregulation of immune responses after animals have been exposed to either homologous or related strains before the delivery of heterologous antigen using a Salmonella vector. A study by Metzger and co-workers on human volunteers using Salmonella Typhi as a vector suggested that there was no change in the T cell immune response against the heterologous antigen in human volunteers who were exposed to empty vector in comparison with volunteers who were immunologically naive of the vector strain (Metzger et al., 2004). In these subjects, humoral responses were moderately elevated in pre-exposed individuals. Similarly, Saxena et al. (2009) indicated higher humoral and T cell responses in mice pre-exposed to homologous or heterologous Salmonella strains. The interleukin 4 (IL4) response was significantly higher when the animal host was exposed to the homologous strain, whereas pre-exposure to a related species did not have such an impact on IL4 responses. Conversely interferon (IFN)-γ responses were higher, irrespective of the strain to which mice were pre-exposed. This study also indicated that the presence of homologous or heterologous opsonizing antibodies leads to a higher uptake of Salmonella by macrophages in vitro, which may explain the higher immune responses in exposed mice. As may be expected, uptake was higher when homologous sera were used as the opsonin rather than heterologous sera. This is depicted in Fig. 2.

Fig. 2.
Uptake of STM-1 by J774 macrophages, relative to the highest uptake percentage. [filled lozenge], Opsonized with naive sera; [filled triangle], opsonized with serum from mice exposed to Salmonella enteriditis; [filled square], opsonized with serum from mice exposed to STM-1. ...

Conversely, there are reports that indicate that pre-existing immunity against the bacterial vector downregulates immune responses against the delivered heterologous antigen using similar or related vectors. Attridge and co-workers reported that the presence of immunity against the bacterial vector prior to the delivery of vectored antigenic protein can downregulate immune responses in mice against the delivered antigen (Attridge et al., 1997). Similar results were reported by Roberts et al. (1999) and Vindurampulle & Attridge (2003a, b). However, the latter authors found that the hypo-responsiveness could be largely eliminated by exposing animals to the foreign antigen prior to vector-priming (Vindurampulle & Attridge, 2003b). Unfortunately, this would appear to be impractical for an immunization regimen!

A study presented by Gahan et al. (2008) immunized mice with S. Typhimurium expressing C fragment of tetanus toxin antigen from an expression plasmid or as a DNA vaccine. Vaccinated mice developed humoral responses to LPS and tetC (for the plasmid-bearing vaccines). Animals from all groups (including a previously unvaccinated group) were immunized on day 182 with Salmonella expressing tetC. At this time, the anti-LPS and tetC titres were beginning to wane. Fourteen days after the second immunization, the colonization of various mouse organs was assessed. The ability to colonize was found to be significantly reduced in groups that had been previously vaccinated with Salmonella. In view of this finding, it was perhaps not surprising that at day 210 the LPS titres were not significantly different between groups receiving one or two vaccinations. More interestingly, mice that had been primed with Salmonella alone, and then boosted with Salmonella expressing tetC, induced much lower anti-tetC responses than mice that had not been primed. This argues strongly that prior immunological immunity to the vector can seriously dampen subsequent antigen-specific humoral responses. Whether the same is true for cellular responses was not evaluated.

Other studies have evaluated cellular responses. A study by Sevil Domènech and colleagues reported that pre-existing anti-vector immunity seriously compromises CD8+ responses in mice when exposed to a similar strain used as vector (Sevil Domènech et al., 2007). In contrast, another study by the same authors reported that animals exposed to related vectors induce much higher CD8+ responses when compared with animals which do not have any pre-existing Salmonella immunity (Sevil Domènech et al., 2008). The difference between these two studies was that in the first, the prime and boost were with identical serovars, while in the second study, different serovars were used. This may point to a way of avoiding downregulation of CD8 responses by pre-existing immunity. This is important, as one of the advantages of using Salmonella (an intracellular pathogen) is that strong cellular immune responses can be induced.

It must be noted that in the case of Salmonella vaccines, effects other than strictly immunological responses (particularly adaptive responses) should be considered. In the context of innate immunity, it was shown that administration of non-virulent Salmonella to gnobiotic pigs eliminated disease following challenge with a virulent strain (Foster et al., 2003). Interestingly, protection was not by competitive exclusion, as the virulent strain was in high numbers in the gut but did not distribute systemically. The protection was proposed to be mediated by the infiltration of a large number of polymorphonuclear leukocytes into the gut, and although perhaps impractical as a general prophylactic (as the time between vaccination and infection is short), this may be an option for short-term or perhaps therapeutic vaccination (as reviewed by Foster et al., 2012).

Chickens (Gallus gallus) are a natural animal reservoir for Salmonella, which makes them an important source of Salmonella-associated gastroenteritis in humans. The ability to use oral Salmonella vaccines to immunize against heterologous pathogens would be of enormous benefit to the poultry industry in both broiler and layer flocks. Both vertical and horizontal transmission is associated with Salmonella in chickens (Liljebjelke et al., 2005). Vertical transmission via in ovo transmission is particularly important, because if there is prior exposure to the vaccine strain, subsequent vaccination using an oral Salmonella vector could be severely compromised. A considerable number of studies on cross-protective immunity and competitive exclusion have been undertaken in chickens. Protective cross-reactive immunity against Salmonella strains has been demonstrated against both homologous and heterologous challenges (Beal et al., 2006), although cross-serogroup protection was not strong. Furthermore, a recent study reported that pre-treatment of newly hatched chickens with different Salmonella strains could produce a complete invasion–inhibition effect on any subsequent exposure to both homologous and heterologous strains (Methner et al., 2010). Pre-exposure with a highly invasive form of Salmonella Enteritidis caused a large influx of heterophils to the caecal mucosa in 1-day-old chicks, and subsequent heterologous caecal colonization was inhibited for a period of 48 h (Methner et al., 2010). The implications of this kind of colonization-inhibition study on the immunological status of the affected chickens are yet to be fully elucidated. It should be noted that the studies listed in Tables 1 and and22 are controlled laboratory studies, with the possibility of a competitive exclusion component to immunity not discussed.

Table 2.
Different effects of pre-existing immunity on the efficacy of recombinant viral vaccine vectors

Similarly studies of L. monocytogenes and the effects of pre-existing immune responses indicate conflicting results. A study by Bouwer et al. (1999) indicates that pre-existing immune responses against the Listeria vector do not diminish immune responses against the delivered heterologous antigen, and a similar study by Starks et al. (2004) also concluded that prior exposure of mice to the empty Listeria vector did not influence anti-cancer immune responses when a similar mutant was used as a carrier of a melanoma cancer antigen. Similar findings were reported by Whitney et al. (2011) in rhesus macaques in which L. monocytyogens was used as a carrier of gag-HIV antigen. Conversely, studies by Stevens et al. (2005) in which L. monocytogens was used to deliver feline immunodeficiency virus (FIV) gag protein and as a carrier of DNA vaccines to vaccinate cats against FIV envelope protein indicated lower immune responses against the delivered antigen in cats exposed to empty Listeria vector in comparison with naive animals (Stevens et al., 2005). Similar findings have been reported by Tvinnereim et al. (2002) and Leong et al. (2009). However, taken together, these studies conclude that prior exposure of host animals to empty vector does not abrogate immune responses to the vectored antigen, but only reduces them somewhat. Only the study by Vijh et al. (1999) indicated that exposure to the empty vector may completely abrogate immune responses against the delivered antigens (Vijh et al., 1999). However, these studies also indicate that downregulation of antigen-specific immune responses is highly dependent on dose and time. Leong et al. (2009) also demonstrated that the negative impact of vector-specific immune responses can also be countered by repeated immunization with the same vaccine and dose; this in effect leads to higher priming of naive T cells against the delivered antigen. Of course, such repeated vaccination may not be practicable in real-world situations.

Effects of prior immunological exposure to vectors – viral vectors

Despite the many advantages which viral vectoring can offer, pre-existing immunity is a major obstacle of many viral-vectored vaccines, such as Ad serotype 5 or herpes simplex virus type 1 (HSV-1), where the rate of seroprevalence to these viruses is very high [40–45 % and 70 % (or more) of the US population, respectively] (Hocknell et al., 2002; Pichla-Gollon et al., 2009). Vector-specific antibodies may impede the induction of immune responses to the vaccine-encoded antigens, as they may reduce the dose and time of exposure of the target cells to the vaccinated antigens (Pichla-Gollon et al., 2009; Pine et al., 2011). In a large-scale clinical trial (STEP) of an Ad serotype 5 (AdHu5)-based HIV-1 vaccine, the vaccines showed a lack of efficacy and tended to increase the risk of HIV-1 infection in vaccine recipients who had pre-existing neutralizing antibodies to AdHu5 (Buchbinder et al., 2008). For an HSV-1-based vector vaccine, it has been demonstrated that pre-existing anti-HSV-1 immunity reduced, but did not abolish, humoral and cellular immune responses against the vaccine-encoded antigen (Hocknell et al., 2002; Lauterbach et al., 2005). However, Brockman and Knipe found that the induction of durable antibody responses and cellular proliferative responses to HSV-encoded antigen were not affected by prior HSV immunity (Brockman & Knipe, 2002). Similarly, pre-existing immunity to poliovirus has little effect on vaccine efficacy in a poliovirus-vectored vaccine (Mandl et al., 2001). Different effects of pre-existing immunity on the efficacy of recombinant viral vaccine vectors are summarized in Table 2. There are several approaches to avoiding pre-existing vector immunity, such as the use of vectors derived from non-human sources, using human viruses of rare serotypes (Kahl et al., 2010; Lasaro & Ertl, 2009), heterologous prime–boost approaches (Liu et al., 2008), homologous reimmunization (Steffensen et al., 2012) and removing key neutralizing epitopes on the surface of viral capsid proteins (Gabitzsch & Jones, 2011; Roberts et al., 2006). The inhibitory effect of pre-existing immunity can also be avoided by masking the Ad vector inside dendritic cells (DCs) (Steffensen et al., 2012). In addition, mucosal vaccination or administration of higher vaccine doses can overcome pre-existing immunity problems (Alexander et al., 2012; Belyakov et al., 1999; Priddy et al., 2008; Xiang et al., 2003).

Concluding remarks and perspective

As we search for new vaccine approaches for the array of pathogens for which none is yet available, revisiting proven vaccines and developing these further has gained momentum. Hence, attenuated bacteria and viruses which have a long history of efficacy and safety are being brought into use. While very attractive, a common theme in these experimental approaches has been the limitations that pre-existing immunity to the vector may pose. However, as this examination of the relevant literature shows, there is a rather confusing picture, with some studies in fact indicating that pre-existing immunity may be a friend, rather than foe.

Few studies using viral vectors have reported on the influence of pre-existing immunity on humoral responses. Generally speaking, for bacterial-delivered antigens, the humoral responses were influenced by pre-existing immunity, with slightly more studies finding augmentation rather than diminution. Why is there variation? This may be due to several factors, including the type of Salmonella used and its invasiveness. Dunstan and colleagues tested the ability of six isogenic Salmonella serovar Typhimurium strains harbouring different mutations for their ability to induce immune responses against the C fragment of tetanus toxin and concluded that the strain which had the least ability to colonize Peyer’s patches induced the lowest immune responses (Dunstan et al., 1998).

Similarly, the boosting time and nature of the antigen used might be important. Attridge and colleagues indicated the importance of boosting time. In one experiment, boosting mice at 10 weeks led to complete inhibition of antibody responses against the delivered heterologous antigen; however, when the mice were boosted at 4 weeks, the downregulation of antibody responses was not so prominent (Attridge et al., 1997). A similar study conducted by Kohlers and colleagues shows that boosting at 7 weeks after pre-exposing animals to empty vector leads to lower antigen-specific IgG and secretory IgA responses; however, boosting at 14 weeks leads to higher IgG and secretory IgA responses (Kohler et al., 2000b). This is in conflict with the above result, although it should be mentioned that they used different Salmonella species. Vindurampulle and Attridge also examined the impact of the Salmonella strain and the nature of the antigens used. In their study, they used S. Dublin and Salmonella Stanley aroA mutants to deliver E. coli K88 and LT-B antigens, and concluded that the effect of pre-existing immunity depends on both the strain used and the type of antigen delivered (Vindurampulle & Attridge, 2003b).

All these studies on the effect of pre-existing immunity discuss the impact on humoral responses. Sevil Domenech and colleagues reported that pre-exposing animals to the homologous Salmonella vector leads to a significant reduction in CD8+ responses; however, exposure of animals to a heterologous strain leads to significantly higher CD8+ responses (Sevil Domènech et al., 2007, 2008). Saxena and colleagues also reported that antigen-specific T cell responses were either similar or significantly higher, with no downregulation in T cell responses observed after pre-exposing mice to either homologous or heterologous strains (Saxena et al., 2009).

For viral vectors, the impact of cell-mediated immunity was more pronounced, and as depicted in Table 2, almost always resulted in a reduction in the subsequent immune response. Presumably this is because viruses will induce neutralizing antibody on the first dose, and in subsequent doses this antibody will limit the number of transduced cells, therefore limiting the responses. This is particularly a problem with a common viral vector such as Ad, where a large proportion of the population will have immunological memory against common serotypes (Lasaro & Ertl, 2009). As these authors conclude, it will be possible to utilize such vectors only by developing vaccines from alternative serotypes. It may be that a vector such as attenuated influenza virus, with the ability to easily develop reassortants, will be useful in this context.

In addition, immunological memory in the form of opsonizing antibody certainly plays an important role in the early uptake of Salmonella by macrophages and DC. This may be beneficial, as the live bacterial vector used for delivery purposes harbours mutations in genes encoding proteins responsible for their survival in the animal host. This not only encumbers their ability to cause disease, making them safe live vectors, but also limits the number of replications. The presence of opsonizing antibodies should mean a higher level of bacterial uptake, leading to higher presentation to the immune system and therefore a better immune response. We have previously shown that this is indeed the case (Saxena et al., 2009) (depicted in Fig. 2). It would be of great benefit to address these issues not only in mice but also in other organisms such as chickens, which are the most likely host to be targeted for the use of live Salmonella vectors, specifically where the vaccines are developed for use in livestock and poultry.

To summarize, bacterial vectors such as Salmonella and viral vectors such as Ad show great promise as delivery vehicles for heterologous antigens; however, prior exposure to the vector must be considered. By judicious selection of the strain/serotype it will be possible to avoid the negative effects and it may indeed be possible to positively influence the response, particularly for humoral immunity.


  • Alderton M. R., Fahey K. J., Coloe P. J. (1991. ). Humoral responses and salmonellosis protection in chickens given a vitamin-dependent Salmonella typhimurium mutant. Avian Dis 35, 435–442 10.2307/1591205 [PubMed] [Cross Ref]
  • Alexander J., Ward S., Mendy J., Manayani D. J., Farness P., Avanzini J. B., Guenther B., Garduno F., Jow L. & other authors (2012. ). Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin. PLoS ONE 7, e31177 10.1371/journal.pone.0031177 [PMC free article] [PubMed] [Cross Ref]
  • Appaiahgari M. B., Vrati S. (2010. ). IMOJEV(®): a Yellow fever virus-based novel Japanese encephalitis vaccine. Expert Rev Vaccines 9, 1371–1384 10.1586/erv.10.139 [PubMed] [Cross Ref]
  • Atkins H. S., Morton M., Griffin K. F., Stokes M. G., Nataro J. P., Titball R. W. (2006. ). Recombinant Salmonella vaccines for biodefence. Vaccine 24, 2710–2717 10.1016/j.vaccine.2005.12.046 [PubMed] [Cross Ref]
  • Attridge S. R., Davies R., LaBrooy J. T. (1997. ). Oral delivery of foreign antigens by attenuated Salmonella: consequences of prior exposure to the vector strain. Vaccine 15, 155–162 10.1016/S0264-410X(96)00158-2 [PubMed] [Cross Ref]
  • Bahey-El-Din M., Casey P. G., Griffin B. T., Gahan C. G. (2010. ). Expression of two Listeria monocytogenes antigens (P60 and LLO) in Lactococcus lactis and examination for use as live vaccine vectors. J Med Microbiol 59, 904–912 10.1099/jmm.0.018770-0 [PubMed] [Cross Ref]
  • Bao J. X., Clements J. D. (1991. ). Prior immunologic experience potentiates the subsequent antibody response when Salmonella strains are used as vaccine carriers. Infect Immun 59, 3841–3845 [PMC free article] [PubMed]
  • Basso H., Rohde M., Guzmán C. A. (2000. ). Vectors to achieve selective expression of vaccine antigens within eukaryotic cells using Salmonella spp. as carrier strains. FEMS Microbiol Lett 182, 219–223 10.1111/j.1574-6968.2000.tb08898.x [PubMed] [Cross Ref]
  • Beal R. K., Wigley P., Powers C., Barrow P. A., Smith A. L. (2006. ). Cross-reactive cellular and humoral immune responses to Salmonella enterica serovars Typhimurium and Enteritidis are associated with protection to heterologous re-challenge. Vet Immunol Immunopathol 114, 84–93 10.1016/j.vetimm.2006.07.011 [PubMed] [Cross Ref]
  • Belyakov I. M., Moss B., Strober W., Berzofsky J. A. (1999. ). Mucosal vaccination overcomes the barrier to recombinant vaccinia immunization caused by preexisting poxvirus immunity. Proc Natl Acad Sci U S A 96, 4512–4517 10.1073/pnas.96.8.4512 [PubMed] [Cross Ref]
  • Bermúdez-Humarán L. G., Kharrat P., Chatel J. M., Langella P. (2011. ). Lactococci and lactobacilli as mucosal delivery vectors for therapeutic proteins and DNA vaccines. Microb Cell Fact 10 (Suppl. 1), S4 10.1186/1475-2859-10-S1-S4 [PMC free article] [PubMed] [Cross Ref]
  • Beukema E. L., Brown M. P., Hayball J. D. (2006. ). The potential role of fowlpox virus in rational vaccine design. Expert Rev Vaccines 5, 565–577 10.1586/14760584.5.4.565 [PubMed] [Cross Ref]
  • Bouwer H. G., Shen H., Fan X., Miller J. F., Barry R. A., Hinrichs D. J. (1999. ). Existing antilisterial immunity does not inhibit the development of a Listeria monocytogenes-specific primary cytotoxic T-lymphocyte response. Infect Immun 67, 253–258 [PMC free article] [PubMed]
  • Brockman M. A., Knipe D. M. (2002. ). Herpes simplex virus vectors elicit durable immune responses in the presence of preexisting host immunity. J Virol 76, 3678–3687 10.1128/JVI.76.8.3678-3687.2002 [PMC free article] [PubMed] [Cross Ref]
  • Brockstedt D. G., Giedlin M. A., Leong M. L., Bahjat K. S., Gao Y., Luckett W., Liu W., Cook D. N., Portnoy D. A., Dubensky T. W., Jr (2004. ). Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A 101, 13832–13837 10.1073/pnas.0406035101 [PubMed] [Cross Ref]
  • Buchbinder S. P., Mehrotra D. V., Duerr A., Fitzgerald D. W., Mogg R., Li D., Gilbert P. B., Lama J. R., Marmor M. & other authors (2008. ). Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 10.1016/S0140-6736(08)61591-3 [PMC free article] [PubMed] [Cross Ref]
  • Chengalvala M. V., Bhat B. M., Bhat R., Lubeck M. D., Mizutani S., Davis A. R., Hung P. P. (1994. ). Immunogenicity of high expression adenovirus-hepatitis B virus recombinant vaccines in dogs. J Gen Virol 75, 125–131 10.1099/0022-1317-75-1-125 [PubMed] [Cross Ref]
  • Cossart P., Mengaud J. (1989. ). Listeria monocytogenes. A model system for the molecular study of intracellular parasitism. Mol Biol Med 6, 463–474 [PubMed]
  • Dougan G., Hormaeche C. E., Maskell D. J. (1987. ). Live oral Salmonella vaccines: potential use of attenuated strains as carriers of heterologous antigens to the immune system. Parasite Immunol 9, 151–160 10.1111/j.1365-3024.1987.tb00496.x [PubMed] [Cross Ref]
  • Draper S. J., Heeney J. L. (2010. ). Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol 8, 62–73 10.1038/nrmicro2240 [PubMed] [Cross Ref]
  • Dunstan S. J., Simmons C. P., Strugnell R. A. (1998. ). Comparison of the abilities of different attenuated Salmonella typhimurium strains to elicit humoral immune responses against a heterologous antigen. Infect Immun 66, 732–740 [PMC free article] [PubMed]
  • Esteban M. (2009. ). Attenuated poxvirus vectors MVA and NYVAC as promising vaccine candidates against HIV/AIDS. Hum Vaccin 5, 867–871 [PubMed]
  • Fitzgerald J. C., Gao G. P., Reyes-Sandoval A., Pavlakis G. N., Xiang Z. Q., Wlazlo A. P., Giles-Davis W., Wilson J. M., Ertl H. C. (2003. ). A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag. J Immunol 170, 1416–1422 [PubMed]
  • Foster N., Lovell M. A., Marston K. L., Hulme S. D., Frost A. J., Bland P., Barrow P. A. (2003. ). Rapid protection of gnotobiotic pigs against experimental salmonellosis following induction of polymorphonuclear leukocytes by avirulent Salmonella enterica. Infect Immun 71, 2182–2191 10.1128/IAI.71.4.2182-2191.2003 [PMC free article] [PubMed] [Cross Ref]
  • Foster N., Berndt A., Lalmanach A. C., Methner U., Pasquali P., Rychlik I., Velge P., Zhou X., Barrow P. (2012. ). Emergency and therapeutic vaccination – is stimulating innate immunity an option? Res Vet Sci 93, 7–12 10.1016/j.rvsc.2011.05.018 [PubMed] [Cross Ref]
  • Gabitzsch E. S., Jones F. R. (2011. ). New recombinant Ad5 vector overcomes Ad5 immunity allowing for multiple safe, homologous immunizations. J Clin Cell Immunol S4, 001
  • Gahan M. E., Webster D. E., Wijburg O. L., Wesselingh S. L., Strugnell R. A. (2008. ). Impact of prior immunological exposure on vaccine delivery by Salmonella enterica serovar Typhimurium. Vaccine 26, 6212–6220 10.1016/j.vaccine.2008.09.060 [PubMed] [Cross Ref]
  • Gao W., Soloff A. C., Lu X., Montecalvo A., Nguyen D. C., Matsuoka Y., Robbins P. D., Swayne D. E., Donis R. O. & other authors (2006. ). Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization. J Virol 80, 1959–1964 10.1128/JVI.80.4.1959-1964.2006 [PMC free article] [PubMed] [Cross Ref]
  • Gentschev I., Dietrich G., Spreng S., Kolb-Mäurer A., Brinkmann V., Grode L., Hess J., Kaufmann S. H., Goebel W. (2001. ). Recombinant attenuated bacteria for the delivery of subunit vaccines. Vaccine 19, 2621–2628 10.1016/S0264-410X(00)00502-8 [PubMed] [Cross Ref]
  • Gómez C. E., Nájera J. L., Krupa M., Esteban M. (2008. ). The poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer. Curr Gene Ther 8, 97–120 10.2174/156652308784049363 [PubMed] [Cross Ref]
  • Guleria I., Teitelbaum R., McAdam R. A., Kalpana G., Jacobs W. R., Jr, Bloom B. R. (1996. ). Auxotrophic vaccines for tuberculosis. Nat Med 2, 334–337 10.1038/nm0396-334 [PubMed] [Cross Ref]
  • Hashimoto M., Boyer J. L., Hackett N. R., Wilson J. M., Crystal R. G. (2005. ). Induction of protective immunity to anthrax lethal toxin with a nonhuman primate adenovirus-based vaccine in the presence of preexisting anti-human adenovirus immunity. Infect Immun 73, 6885–6891 10.1128/IAI.73.10.6885-6891.2005 [PMC free article] [PubMed] [Cross Ref]
  • Hocknell P. K., Wiley R. D., Wang X., Evans T. G., Bowers W. J., Hanke T., Federoff H. J., Dewhurst S. (2002. ). Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responses. J Virol 76, 5565–5580 10.1128/JVI.76.11.5565-5580.2002 [PMC free article] [PubMed] [Cross Ref]
  • Hsu K.-H., Lubeck M. D., Davis A. R., Bhat R. A., Selling B. H., Bhat B. M., Mizutani S., Murphy B. R., Collins P. L. & other authors (1992. ). Immunogenicity of recombinant adenovirus-respiratory syncytial virus vaccines with adenovirus types 4, 5, and 7 vectors in dogs and a chimpanzee. J Infect Dis 166, 769–775 10.1093/infdis/166.4.769 [PubMed] [Cross Ref]
  • Husseiny M. I., Hensel M. (2008. ). Construction of highly attenuated Salmonella enterica serovar Typhimurium live vectors for delivering heterologous antigens by chromosomal integration. Microbiol Res 163, 605–615 10.1016/j.micres.2006.10.003 [PubMed] [Cross Ref]
  • Innocentin S., Guimarães V., Miyoshi A., Azevedo V., Langella P., Chatel J. M., Lefèvre F. (2009. ). Lactococcus lactis expressing either Staphylococcus aureus fibronectin-binding protein A or Listeria monocytogenes internalin A can efficiently internalize and deliver DNA in human epithelial cells. Appl Environ Microbiol 75, 4870–4878 10.1128/AEM.00825-09 [PMC free article] [PubMed] [Cross Ref]
  • Jensen E. R., Shen H., Wettstein F. O., Ahmed R., Miller J. F. (1997. ). Recombinant Listeria monocytogenes as a live vaccine vehicle and a probe for studying cell-mediated immunity. Immunol Rev 158, 147–157 10.1111/j.1600-065X.1997.tb01001.x [PubMed] [Cross Ref]
  • Jespersgaard C., Zhang P., Hajishengallis G., Russell M. W., Michalek S. M. (2001. ). Effect of attenuated Salmonella enterica serovar Typhimurium expressing a Streptococcus mutans antigen on secondary responses to the cloned protein. Infect Immun 69, 6604–6611 10.1128/IAI.69.11.6604-6611.2001 [PMC free article] [PubMed] [Cross Ref]
  • Jiang P., Jiang W., Li Y., Wu S., Xu J. (2004. ). Humoral immune response induced by oral administration of S. typhimurium containing a DNA vaccine against porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol 102, 321–328 10.1016/j.vetimm.2004.09.014 [PubMed] [Cross Ref]
  • Johnson P. V., Blair B. M., Zeller S., Kotton C. N., Hohmann E. L. (2011. ). Attenuated Listeria monocytogenes vaccine vectors expressing influenza A nucleoprotein: preclinical evaluation and oral inoculation of volunteers. Microbiol Immunol 55, 304–317 10.1111/j.1348-0421.2011.00322.x [PMC free article] [PubMed] [Cross Ref]
  • Kahl C. A., Bonnell J., Hiriyanna S., Fultz M., Nyberg-Hoffman C., Chen P., King C. R., Gall J. G. (2010. ). Potent immune responses and in vitro pro-inflammatory cytokine suppression by a novel adenovirus vaccine vector based on rare human serotype 28. Vaccine 28, 5691–5702 10.1016/j.vaccine.2010.06.050 [PMC free article] [PubMed] [Cross Ref]
  • Kaufmann S. H. (1993. ). Immunity to intracellular bacteria. Annu Rev Immunol 11, 129–163 10.1146/annurev.iy.11.040193.001021 [PubMed] [Cross Ref]
  • Killeen K., DiRita V. (2000. ). Live attenuated bacterial vaccines. In New Vaccine Technologies. Edited by Ellis R., editor. Georgetown, TX: Landes Bioscience
  • Kirby A. C., Sundquist M., Wick M. J. (2004. ). In vivo compartmentalization of functionally distinct, rapidly responsive antigen-specific T-cell populations in DNA-immunized or Salmonella enterica serovar Typhimurium-infected mice. Infect Immun 72, 6390–6400 10.1128/IAI.72.11.6390-6400.2004 [PMC free article] [PubMed] [Cross Ref]
  • Kohler J. J., Pathangey L., Hasona A., Progulske-Fox A., Brown T. A. (2000a. ). Long-term immunological memory induced by recombinant oral Salmonella vaccine vectors. Infect Immun 68, 4370–4373 10.1128/IAI.68.7.4370-4373.2000 [PMC free article] [PubMed] [Cross Ref]
  • Kohler J. J., Pathangey L. B., Gillespie S. R., Brown T. A. (2000b. ). Effect of preexisting immunity to Salmonella on the immune response to recombinant Salmonella enterica serovar Typhimurium expressing a Porphyromonas gingivalis hemagglutinin. Infect Immun 68, 3116–3120 10.1128/IAI.68.6.3116-3120.2000 [PMC free article] [PubMed] [Cross Ref]
  • Lasaro M. O., Ertl H. C. (2009. ). New insights on adenovirus as vaccine vectors. Mol Ther 17, 1333–1339 10.1038/mt.2009.130 [PubMed] [Cross Ref]
  • Lauterbach H., Ried C., Epstein A. L., Marconi P., Brocker T. (2005. ). Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity. J Gen Virol 86, 2401–2410 10.1099/vir.0.81104-0 [PubMed] [Cross Ref]
  • Leong M. L., Hampl J., Liu W., Mathur S., Bahjat K. S., Luckett W., Dubensky T. W., Jr, Brockstedt D. G. (2009. ). Impact of preexisting vector-specific immunity on vaccine potency: characterization of Listeria monocytogenes-specific humoral and cellular immunity in humans and modeling studies using recombinant vaccines in mice. Infect Immun 77, 3958–3968 10.1128/IAI.01274-08 [PMC free article] [PubMed] [Cross Ref]
  • Levine M. M., Galen J., Barry E., Noriega F., Tacket C., Sztein M., Chatfield S., Dougan G., Losonsky G., Kotloff K. (1997. ). Attenuated Salmonella typhi and Shigella as live oral vaccines and as live vectors. Behring Inst Mitt 98, 120–123 [PubMed]
  • Liljebjelke K. A., Hofacre C. L., Liu T., White D. G., Ayers S., Young S., Maurer J. J. (2005. ). Vertical and horizontal transmission of Salmonella within integrated broiler production system. Foodborne Pathog Dis 2, 90–102 10.1089/fpd.2005.2.90 [PubMed] [Cross Ref]
  • Limbach K. J., Richie T. L. (2009. ). Viral vectors in malaria vaccine development. Parasite Immunol 31, 501–519 10.1111/j.1365-3024.2009.01141.x [PubMed] [Cross Ref]
  • Liu J., Ewald B. A., Lynch D. M., Denholtz M., Abbink P., Lemckert A. A., Carville A., Mansfield K. G., Havenga M. J. & other authors (2008. ). Magnitude and phenotype of cellular immune responses elicited by recombinant adenovirus vectors and heterologous prime-boost regimens in rhesus monkeys. J Virol 82, 4844–4852 10.1128/JVI.02616-07 [PMC free article] [PubMed] [Cross Ref]
  • Lo W. F., Ong H., Metcalf E. S., Soloski M. J. (1999. ). T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules. J Immunol 162, 5398–5406 [PubMed]
  • Mandl S., Hix L., Andino R. (2001. ). Preexisting immunity to poliovirus does not impair the efficacy of recombinant poliovirus vaccine vectors. J Virol 75, 622–627 10.1128/JVI.75.2.622-627.2001 [PMC free article] [PubMed] [Cross Ref]
  • Mastroeni P., Chabalgoity J. A., Dunstan S. J., Maskell D. J., Dougan G. (2001. ). Salmonella: immune responses and vaccines. Vet J 161, 132–164 10.1053/tvjl.2000.0502 [PubMed] [Cross Ref]
  • McElrath M. J., De Rosa S. C., Moodie Z., Dubey S., Kierstead L., Janes H., Defawe O. D., Carter D. K., Hural J. & other authors (2008. ). HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372, 1894–1905 10.1016/S0140-6736(08)61592-5 [PMC free article] [PubMed] [Cross Ref]
  • Methner U., Barrow P. A., Berndt A. (2010. ). Induction of a homologous and heterologous invasion–inhibition effect after administration of Salmonella strains to newly hatched chicks. Vaccine 28, 6958–6963 10.1016/j.vaccine.2010.08.050 [PubMed] [Cross Ref]
  • Metzger W. G., Mansouri E., Kronawitter M., Diescher S., Soerensen M., Hurwitz R., Bumann D., Aebischer T., Von Specht B. U., Meyer T. F. (2004. ). Impact of vector-priming on the immunogenicity of a live recombinant Salmonella enterica serovar Typhi Ty21a vaccine expressing urease A and B from Helicobacter pylori in human volunteers. Vaccine 22, 2273–2277 10.1016/j.vaccine.2003.11.020 [PubMed] [Cross Ref]
  • Minke J. M., Audonnet J. C., Fischer L. (2004. ). Equine viral vaccines: the past, present and future. Vet Res 35, 425–443 10.1051/vetres:2004019 [PubMed] [Cross Ref]
  • Mittrücker H. W., Kaufmann S. H. (2000. ). Immune response to infection with Salmonella typhimurium in mice. J Leukoc Biol 67, 457–463 [PubMed]
  • Mooij P., Balla-Jhagjhoorsingh S. S., Koopman G., Beenhakker N., van Haaften P., Baak I., Nieuwenhuis I. G., Kondova I., Wagner R. & other authors (2008. ). Differential CD4+ versus CD8+ T-cell responses elicited by different poxvirus-based human immunodeficiency virus type 1 vaccine candidates provide comparable efficacies in primates. J Virol 82, 2975–2988 10.1128/JVI.02216-07 [PMC free article] [PubMed] [Cross Ref]
  • Nauciel C. (1990. ). Role of CD4+ T cells and T-independent mechanisms in acquired resistance to Salmonella typhimurium infection. J Immunol 145, 1265–1269 [PubMed]
  • Pamer E. G., Sijts A. J., Villanueva M. S., Busch D. H., Vijh S. (1997. ). MHC class I antigen processing of Listeria monocytogenes proteins: implications for dominant and subdominant CTL responses. Immunol Rev 158, 129–136 10.1111/j.1600-065X.1997.tb00999.x [PubMed] [Cross Ref]
  • Pandey A., Singh N., Vemula S. V., Couëtil L., Katz J. M., Donis R., Sambhara S., Mittal S. K. (2012. ). Impact of preexisting adenovirus vector immunity on immunogenicity and protection conferred with an adenovirus-based H5N1 influenza vaccine. PLoS ONE 7, e33428 10.1371/journal.pone.0033428 [PMC free article] [PubMed] [Cross Ref]
  • Peters C., Peng X., Douven D., Pan Z. K., Paterson Y. (2003. ). The induction of HIV Gag-specific CD8+ T cells in the spleen and gut-associated lymphoid tissue by parenteral or mucosal immunization with recombinant Listeria monocytogenes HIV Gag. J Immunol 170, 5176–5187 [PubMed]
  • Pichla-Gollon S. L., Lin S. W., Hensley S. E., Lasaro M. O., Herkenhoff-Haut L., Drinker M., Tatsis N., Gao G. P., Wilson J. M. & other authors (2009. ). Effect of preexisting immunity on an adenovirus vaccine vector: in vitro neutralization assays fail to predict inhibition by antiviral antibody in vivo. J Virol 83, 5567–5573 10.1128/JVI.00405-09 [PMC free article] [PubMed] [Cross Ref]
  • Pine S. O., Kublin J. G., Hammer S. M., Borgerding J., Huang Y., Casimiro D. R., McElrath M. J. (2011. ). Pre-existing adenovirus immunity modifies a complex mixed Th1 and Th2 cytokine response to an Ad5/HIV-1 vaccine candidate in humans. PLoS ONE 6, e18526 10.1371/journal.pone.0018526 [PMC free article] [PubMed] [Cross Ref]
  • Priddy F. H., Brown D., Kublin J., Monahan K., Wright D. P., Lalezari J., Santiago S., Marmor M., Lally M. & other authors (2008. ). Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. Clin Infect Dis 46, 1769–1781 10.1086/587993 [PubMed] [Cross Ref]
  • Radosevic K., Wieland C. W., Rodriguez A., Weverling G. J., Mintardjo R., Gillissen G., Vogels R., Skeiky Y. A., Hone D. M. & other authors (2007. ). Protective immune responses to a recombinant adenovirus type 35 tuberculosis vaccine in two mouse strains: CD4 and CD8 T-cell epitope mapping and role of gamma interferon. Infect Immun 75, 4105–4115 10.1128/IAI.00004-07 [PMC free article] [PubMed] [Cross Ref]
  • Rimmelzwaan G. F., Sutter G. (2009. ). Candidate influenza vaccines based on recombinant modified vaccinia virus Ankara. Expert Rev Vaccines 8, 447–454 10.1586/erv.09.4 [PubMed] [Cross Ref]
  • Roberts M., Bacon A., Li J., Chatfield S. (1999. ). Prior immunity to homologous and heterologous Salmonella serotypes suppresses local and systemic anti-fragment C antibody responses and protection from tetanus toxin in mice immunized with Salmonella strains expressing fragment C. Infect Immun 67, 3810–3815 [PMC free article] [PubMed]
  • Roberts D. M., Nanda A., Havenga M. J., Abbink P., Lynch D. M., Ewald B. A., Liu J., Thorner A. R., Swanson P. E. & other authors (2006. ). Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity. Nature 441, 239–243 10.1038/nature04721 [PubMed] [Cross Ref]
  • Rollier C. S., Reyes-Sandoval A., Cottingham M. G., Ewer K., Hill A. V. (2011. ). Viral vectors as vaccine platforms: deployment in sight. Curr Opin Immunol 23, 377–382 10.1016/j.coi.2011.03.006 [PubMed] [Cross Ref]
  • Saxena M., Coloe P. J., Smooker P. M. (2009. ). Influence of promoter, gene copy number, and preexisting immunity on humoral and cellular responses to a vectored antigen delivered by a Salmonella enterica vaccine. Clin Vaccine Immunol 16, 78–87 10.1128/CVI.00253-08 [PMC free article] [PubMed] [Cross Ref]
  • Schirrmacher V., Fournier P. (2009. ). Newcastle disease virus: a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol Biol 542, 565–605 10.1007/978-1-59745-561-9_30 [PubMed] [Cross Ref]
  • Sevil Domènech V. E., Panthel K., Meinel K. M., Winter S. E., Rüssmann H. (2007. ). Pre-existing anti-Salmonella vector immunity prevents the development of protective antigen-specific CD8 T-cell frequencies against murine listeriosis. Microbes Infect 9, 1447–1453 10.1016/j.micinf.2007.07.010 [PubMed] [Cross Ref]
  • Sevil Domènech V. E., Panthel K., Winter S. E., Rüssmann H. (2008. ). Heterologous prime–boost immunizations with different Salmonella serovars for enhanced antigen-specific CD8 T-cell induction. Vaccine 26, 1879–1886 10.1016/j.vaccine.2008.01.044 [PubMed] [Cross Ref]
  • Shen H., Slifka M. K., Matloubian M., Jensen E. R., Ahmed R., Miller J. F. (1995. ). Recombinant Listeria monocytogenes as a live vaccine vehicle for the induction of protective anti-viral cell-mediated immunity. Proc Natl Acad Sci U S A 92, 3987–3991 10.1073/pnas.92.9.3987 [PubMed] [Cross Ref]
  • Shiver J. W., Fu T. M., Chen L., Casimiro D. R., Davies M. E., Evans R. K., Zhang Z. Q., Simon A. J., Trigona W. L. & other authors (2002. ). Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335 10.1038/415331a [PubMed] [Cross Ref]
  • Sirard J. C., Niedergang F., Kraehenbuhl J. P. (1999. ). Live attenuated Salmonella: a paradigm of mucosal vaccines. Immunol Rev 171, 5–26 10.1111/j.1600-065X.1999.tb01340.x [PubMed] [Cross Ref]
  • Starks H., Bruhn K. W., Shen H., Barry R. A., Dubensky T. W., Brockstedt D., Hinrichs D. J., Higgins D. E., Miller J. F. & other authors (2004. ). Listeria monocytogenes as a vaccine vector: virulence attenuation or existing antivector immunity does not diminish therapeutic efficacy. J Immunol 173, 420–427 [PubMed]
  • Steffensen M. A., Jensen B. A. H., Holst P. J., Bassi M. R., Christensen J. P., Thomsen A. R. (2012. ). Pre-existing vector immunity does not prevent replication deficient adenovirus from inducing efficient CD8 T-cell memory and recall responses. PLoS ONE 7, e34884 10.1371/journal.pone.0034884 [PMC free article] [PubMed] [Cross Ref]
  • Stevens R., Lavoy A., Nordone S., Burkhard M., Dean G. A. (2005. ). Pre-existing immunity to pathogenic Listeria monocytogenes does not prevent induction of immune responses to feline immunodeficiency virus by a novel recombinant Listeria monocytogenes vaccine. Vaccine 23, 1479–1490 10.1016/j.vaccine.2004.09.033 [PubMed] [Cross Ref]
  • Stoyanov C. T., Boscardin S. B., Deroubaix S., Barba-Spaeth G., Franco D., Nussenzweig R. S., Nussenzweig M., Rice C. M. (2010. ). Immunogenicity and protective efficacy of a recombinant yellow fever vaccine against the murine malarial parasite Plasmodium yoelii. Vaccine 28, 4644–4652 10.1016/j.vaccine.2010.04.071 [PMC free article] [PubMed] [Cross Ref]
  • Tobias J., Svennerholm A. M. (2012. ). Strategies to overexpress enterotoxigenic Escherichia coli (ETEC) colonization factors for the construction of oral whole-cell inactivated ETEC vaccine candidates. Appl Microbiol Biotechnol 93, 2291–2300 10.1007/s00253-012-3930-6 [PubMed] [Cross Ref]
  • Tobias J., Lebens M., Bölin I., Wiklund G., Svennerholm A. M. (2008. ). Construction of non-toxic Escherichia coli and Vibrio cholerae strains expressing high and immunogenic levels of enterotoxigenic E. coli colonization factor I fimbriae. Vaccine 26, 743–752 10.1016/j.vaccine.2007.12.009 [PubMed] [Cross Ref]
  • Tobias J., Holmgren J., Hellman M., Nygren E., Lebens M., Svennerholm A. M. (2010. ). Over-expression of major colonization factors of enterotoxigenic Escherichia coli, alone or together, on non-toxigenic E. coli bacteria. Vaccine 28, 6977–6984 10.1016/j.vaccine.2010.08.047 [PubMed] [Cross Ref]
  • Tvinnereim A. R., Hamilton S. E., Harty J. T. (2002. ). CD8+-T-cell response to secreted and nonsecreted antigens delivered by recombinant Listeria monocytogenes during secondary infection. Infect Immun 70, 153–162 10.1128/IAI.70.1.153-162.2002 [PMC free article] [PubMed] [Cross Ref]
  • Vemula S. V., Mittal S. K. (2010. ). Production of adenovirus vectors and their use as a delivery system for influenza vaccines. Expert Opin Biol Ther 10, 1469–1487 10.1517/14712598.2010.519332 [PMC free article] [PubMed] [Cross Ref]
  • Vijh S., Pilip I. M., Pamer E. G. (1999. ). Noncompetitive expansion of cytotoxic T lymphocytes specific for different antigens during bacterial infection. Infect Immun 67, 1303–1309 [PMC free article] [PubMed]
  • Vindurampulle C. J., Attridge S. R. (2003a. ). Vector priming reduces the immunogenicity of Salmonella-based vaccines in Nramp1+/+ mice. Infect Immun 71, 2258–2261 10.1128/IAI.71.4.2258-2261.2003 [PMC free article] [PubMed] [Cross Ref]
  • Vindurampulle C. J., Attridge S. R. (2003b. ). Impact of vector priming on the immunogenicity of recombinant Salmonella vaccines. Infect Immun 71, 287–297 10.1128/IAI.71.1.287-297.2003 [PMC free article] [PubMed] [Cross Ref]
  • Ward S. J., Douce G., Figueiredo D., Dougan G., Wren B. W. (1999. ). Immunogenicity of a Salmonella typhimurium aroA aroD vaccine expressing a nontoxic domain of Clostridium difficile toxin A. Infect Immun 67, 2145–2152 [PMC free article] [PubMed]
  • Weli S. C., Tryland M. (2011. ). Avipoxviruses: infection biology and their use as vaccine vectors. Virol J 8, 49 10.1186/1743-422X-8-49 [PMC free article] [PubMed] [Cross Ref]
  • Wells J. M., Mercenier A. (2008. ). Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria. Nat Rev Microbiol 6, 349–362 10.1038/nrmicro1840 [PubMed] [Cross Ref]
  • Weyer J., Rupprecht C. E., Nel L. H. (2009. ). Poxvirus-vectored vaccines for rabies—a review. Vaccine 27, 7198–7201 10.1016/j.vaccine.2009.09.033 [PubMed] [Cross Ref]
  • Whitney J. B., Mirshahidi S., Lim S. Y., Goins L., Ibegbu C. C., Anderson D. C., Raybourne R. B., Frankel F. R., Lieberman J., Ruprecht R. M. (2011. ). Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV. J Immune Based Ther Vaccines 9, 2 10.1186/1476-8518-9-2 [PMC free article] [PubMed] [Cross Ref]
  • Whittle B. L., Verma N. K. (1997. ). The immune response to a B-cell epitope delivered by Salmonella is enhanced by prior immunological experience. Vaccine 15, 1737–1740 10.1016/S0264-410X(97)00119-9 [PubMed] [Cross Ref]
  • Xiang Z. Q., Gao G. P., Reyes-Sandoval A., Li Y., Wilson J. M., Ertl H. C. (2003. ). Oral vaccination of mice with adenoviral vectors is not impaired by preexisting immunity to the vaccine carrier. J Virol 77, 10780–10789 10.1128/JVI.77.20.10780-10789.2003 [PMC free article] [PubMed] [Cross Ref]
  • Yin Y., Tian D., Jiao H., Zhang C., Pan Z., Zhang X., Wang X., Jiao X. (2011. ). Pathogenicity and immunogenicity of a mutant strain of Listeria monocytogenes in the chicken infection model. Clin Vaccine Immunol 18, 500–505 10.1128/CVI.00445-10 [PMC free article] [PubMed] [Cross Ref]

Articles from Microbiology are provided here courtesy of Microbiology Society