Toward an effective Staphylococcus vaccine: why have candidates failed and what is the next step?

S. aureus is a leading cause of infection and a major driver of antibiotic resistance. Appropriately, it consistently ranks on the CDC list of ‘THREAT’ pathogens that are in dire need of an effective vaccine [1]. S. aureus immunizations have been studied as early as 1902 [2], but the number of vaccine studies peaked over the past three decades in response to the urgent clinical need, and partly spurred by the success of vaccines targeting bacterial pathogens such as S. pneumoniae and H. influenzae. Unexpectedly, there has not been a successful S. aureus vaccine after approximately 30 completed vaccine trials [3,4]. The reasons behind the failures have been speculated broadly, but there has been no consensus on the cause. This editorial article focuses on a recently published study from our group that demonstrates immune imprinting as a way to reinterpret S. aureus vaccine failures [5].

In this study, we proposed that the reason why staphylococcal vaccines failed in humans and succeeded in mice lies in the early and frequent exposures of humans to S. aureus and the absence of S. aureus exposure in mice [6,7]. We speculated that prior S. aureus exposure leads to reprogramming of the host immune system that makes S. aureus vaccines ineffective. To test our hypothesis, we recapitulated the failed vaccine trial that targeted the highly conserved, iron-regulated surface determinant protein B (IsdB) [8] and showed that IsdB vaccines were highly effective in mice that have not been exposed to S. aureus, but were ineffective when administered to mice previously infected with S. aureus [5].

Further investigation revealed that IsdB-specific antibodies, although abundantly generated in S. aureus pre-exposed mice, were non-neutralizing and had no effect on the opsonophagocytic killing of S. aureus by neutrophils [5]. Immunizing S. aureus-exposed mice with IsdB led to the generation of antibodies that shared these non-protective features, in sharp contrast to the protective antibodies generated by the same vaccine in naïve mice. Effectively, the preferential recall of non-protective B cell clone was the responsible mechanism and doomed the vaccine to failure. These findings largely follow the ‘original antigenic sin’ hypothesis that explains the reduced protective antibody response to influenza strains that have undergone seasonal antigenic drift [9]. Notably, we also found that the recalled non-protective anti-IsdB antibodies further suppressed the efficacy of protective IsdB-specific antibodies by competition. Together, these data provide a mechanistic basis for the significant and unexpected failures of the highly promising IsdB vaccine candidate.

The most pressing query going forward is whether the mechanism underlying IsdB vaccine interference could also explain the failure of other S. aureus vaccines? Specifically, are all imprints non-protective or are there protective classes of antigens that could be exploited to develop protective vaccines? Are there antigens that induce no imprints and yet generate protective immunity when administered as vaccines? Predictive modeling of vaccine success based on the character of antibody imprint would prompt rethinking of our current vaccine development platforms. Hence, we propose that the next set of investigations should focus on the effect of humoral imprints on active and passive immunizations that failed vaccine trials, against both cell-wall associated antigens as well as toxins, which could represent classes of non-protective and protective vaccine antigens, respectively. If the initial assessment of S. aureus vaccines suggests indeed a broader role of immune imprinting in determining S. aureus vaccine outcomes, there would be a greater impetus to explore both basic and clinical aspects of the highly complex system of immune interactions, as, together, they could offer additional clues on how to overcome immune imprinting.

For modeling of chronic human exposure to S. aureus, we have shown that imprinting could be achieved by prior infections induced through the intraperitoneal, intravenous, or subcutaneous route [5]. Alternatively, minipigs are naturally colonized with S. aureus and have demonstrated a lack of efficacy to a capsular polysaccharide vaccine [10] as in human trial [11] and therefore could serve as an attractive vaccine platform.

From a conceptual viewpoint, pathobiont S. aureus has evolved efficient strategies to neutralize adaptive immune defense to coexist with its host. Such strategies could have unintentionally suppressed S. aureus vaccine responses. Hence, a better understanding of why imprints are not protective could provide important clues that advance vaccine development. For example, non-protective IsdB antibodies have increased α2,3 sialylation that leads to reduced ability to promote opsonophagocytic killing of S. aureus by neutrophils [5]. If we determine that this Fc feature is common to non-protective antibodies, Fc glycosylation could be used as a marker for predicting the success of an S. aureus vaccine. Additionally, a common host mechanism that induces increased Fc sialylation could be a target for modulation of vaccine efficacy using adjuvants.

Other areas of potential importance include the investigation of how S. aureus virulence factors influence immune imprint to modify vaccine efficacy, which could lead to selective targeting of S. aureus factors to reduce interference. One well-studied S. aureus factor that modulates humoral immunity is the cell wall associated protein A. This multifunctional factor binds avidly to the Fcγ domain of immunoglobulins to dampen Fab neutralization of S. aureus cell surface antigens and limit opsonophagocytic killing of the pathogen [12]. In addition, Protein A is a superantigen that binds to the variable region of human VH3 encoded antibodies. Binding to the antibodies on B cells can lead to apoptosis as well as skewing of the anti-S. aureus repertoire, both of which reduce anti-S. aureus vaccine efficacy [13,14]. Vaccination against a Protein A variant SpA_KKAA, with amino acids substitutions that abolish binding to Fcγ or Fab Vh3, restored opsonophagocytic killing of S. aureus and promoted the generation of a protective antibody response against a diverse repertoire of staphylococcal antigens [15].

For therapeutics, the modified framework that explains vaccine failures could suggest novel approaches to develop successful vaccines. For example, Montgomery and colleagues have proposed that the identification of subdominant antigens or epitopes could be a way to circumvent immunodominant immune imprinting [16]. In our study, we have shown that vaccines targeting of subdominant or cryptic epitopes on IsdB can be effective even in S. aureus exposed mice [5]. For T cells, Montgomery and colleagues have shown that priming of protective T cells by subdominant epitopes could be inhibited by non-protective dominant epitopes, but the MHC-dependent inhibition could be overcome by careful selection of vaccine antigens [17]. Hence, the mapping of anti-S. aureus T and B cells epitopes and antigens could be an effective strategy to discover subdominant protective epitopes that overcome vaccine interference.

There remain unanswered questions on how to circumvent the modified S. aureus-exposed host environment. For example, could a vaccine administered early in life avoid imprinting? While such an approach makes sense, there may be a short window before the infants are colonized with S. aureus. Additionally, we will need to address if maternally transferred antibodies have a role in masking vaccine antigens and thereby modify vaccine responses. Because of its long history of vaccine failures, a currently favored S. aureus vaccine strategy is the development of vaccines targeting multiple antigens. This approach should address the lack of conserved and dominant antigens across S. aureus strains, that is needed to develop a universal vaccine. Given the coexistence of S. aureus and humans, such dominant antigens would likely induce abundant non-protective imprint and therefore may not be strong vaccine candidates. While several vaccines targeting multiple antigens have been evaluated in clinical trials, it is notable that there has been no report of success using this approach. It could be speculated that adding more antigens may not necessarily improve the odds of developing a working vaccine, as co-administered non-protective antigens could induce cross-suppression of protective S. aureus antigens. Such a hypothesis could be easily tested.

Our study did not address anti-toxin vaccines, which remain a promising vaccine approach given the litany of the literature suggesting that toxins are protective antigens [4]. Since the anti-toxin strategy aims primarily to alleviate immunopathology, the strategy may theoretically be less effective at preventing S. aureus infections, in contrast to strategies that focus on inducing opsonophagocytic clearance of the pathogen. Natural anti-toxin antibodies are also abundant in human sera; thus, vaccines may not offer substantial added benefit. Biofilm plays a particularly important role in hospital-associated infections and should be considered as an important vaccine target [18], but the role of immune imprinting in anti-biofilm vaccination is unclear.

Vaccines that target T cell immunity are another strategy that appears promising. Unlike B cells, which have an unclear role in promoting long-term immunity against S. aureus infections (based on the normal S. aureus infection risk of individuals with B cell deficiency) [19,20], the role of T cells in anti-S. aureus immunity is better established from the higher incidence and severity of staphylococcal infections in patients with Human Immunodeficiency Virus and STAT3 deficiency [21,22]. Hence, induction of protective T cell immunity by vaccination should be explored, although the effect of immune imprinting on T cell vaccination should also be studied.

In summary, traditional vaccine development has heavily relied on pre-clinical testing in laboratory animals that have never seen the target pathogen. Several studies have now challenged the use of naïve mice because their immune response is frequently different from the more complex responses in humans [23]. Our findings of IsdB vaccine interference suggest that pathobionts like S. aureus, through yet defined immune evasion mechanisms, suppress vaccine efficacy. If more broadly demonstrated across other S. aureus vaccines, there may be a need to rethink how host-S. aureus interaction recalibrate vaccine efficacy. Vaccine development may then require retooling and reevaluation to address why S. aureus and a handful of other pathogens have so far defied traditional vaccine development strategies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study received funding from the National Institute of Health grant R01AI127406 (GYL), R01AI144694 (GYL).