ABOVE: Staphylococcus aureus often evades clearance by the host despite numerous innate and adaptive immune strategies and vaccination attempts. JR Caldera

Staphylococcus aureus (S. aureus) has a complicated relationship with humans. While this commensal bacterium colonizes approximately 20-30 percent of human nasal cavities and is a member of the human skin microbiome, S. aureus is also a major opportunistic pathogen, which often causes deadly infections in immunocompromised patients.1,2 Further complicating this relationship is the emergence of several multidrug-resistant strains, which are key threats to public health globally.3 Consequently, a vaccine against S. aureus is of grave importance. However, despite numerous attempts over multiple decades, none of the vaccine candidates effectively prevented S. aureus infections in humans, baffling researchers.

In a recently published Cell Reports Medicine paper, researchers determined that previous exposures to the pathogen affect vaccine efficacy, where they could predict a vaccine’s success by evaluating the antigen type and the pre-existing titer of antibodies against that antigen.4 This information will guide scientists to develop improved vaccines for humans.

“One of the big dilemmas in the field was that we have this vaccine problem,” said George Liu, an immunologist and infectious disease researcher at the University of California, San Diego School of Medicine and author of this study. “There have been probably close to 30 [clinical] trials [with] about 10 or more of these phase two and phase three trials where they really study the efficacy of the vaccines. And all of these wonderful vaccines that work in mice, when they take them to humans, they fail.”

This unsolved problem drove Liu and his team to interrogate the differences between human and mice responses. They suspected that these variations resulted from dissimilar exposure rates. Scientists keep laboratory mice in a relatively sterile environment where they infrequently encounter S. aureus. Conversely, more than 50 percent of infants carry S. aureus in their nasal cavities by the age of two months with exposure continuing throughout their lifetime.5

Photo of this study’s authors, JR Caldera (first on the left), Chih Ming Tsai (second on the left), and George Liu (far right).
George Liu and his team examine the interaction between Staphylococcus aureus and the host’s immune system to develop effective vaccines and therapies against the pathogen. 
JR Caldera

Liu and his team previously replicated a vaccine candidate’s failure by exposing mice to S. aureus before immunization.6 Although the vaccine, which targeted a cell-wall-associated antigen (CWA), induced the animals to make protective antibodies against the pathogen, nonprotective antibodies were also produced and directly competed for antigen binding. These ineffective antibodies were originally generated following earlier encounters with the bacterium, which suggested that this vaccine failed because it prompted the mice to recall a nonprotective immune memory. Additionally, these results correspond to the original antigenic sin hypothesis, which proposed that antibodies produced against a dominant antigen following infection with one influenza strain will predetermine the antibodies generated against a new influenza strain even if they are not protective.7

To establish if this hypothesis could also explain other failed vaccines, Liu and his colleagues examined the characteristics of the pre-existing antibodies and their corresponding antigens in mice that had previously encountered the bacterium. They specifically focused on antibodies against the main CWA or bacterial toxins, which included antigens that were the targets of failed vaccine candidates. The researchers noticed that the antibody titers varied within the sera and considered an antigen to be dominant or subdominant depending on its associated antibody abundance. Then they purified the antibodies and employed in vitro assays to test the ability of the CWA antibodies to opsonize the bacterium and lead to phagocytosis-mediated killing; they also used toxin antibodies to protect cells against toxin-induced lysis. They observed that the CWA antibodies did not effectively facilitate S. aureus killing, which suggested that they were nonprotective. However, the researchers found that the toxin antibodies efficiently neutralized the bacterial toxin.

An illustration of various antibodies targeting antigens on the surface of <em >Staphylococcus aureus</em>.   
George Liu, JR Caldera, and their colleagues established that the concentration of existing protective and nonprotective antibodies generated following earlier exposures to Staphylococcus aureus can affect the success of vaccination.  
JR Caldera

To determine how these properties affected vaccine efficacy, the researchers immunized mice with and without prior exposure to S. aureus with the major antigens. On challenging these mice with the bacteria, the researchers observed that vaccines against dominant toxin antigens protected both naïve animals and those previously exposed to the bacterium. These results suggested that protective imprints do not interfere with active vaccination and that immunization against toxins could be an effective strategy. They also determined that vaccination with dominant CWA antigens reduced the bacterial load in naïve mice but had no effect in experienced mice because the vaccine induced the animals to recall a nonprotective imprint. In contrast, immunization against subdominant CWA antigens successfully protected both experienced and inexperienced mice, which indicates that these antigens could be ideal targets for future vaccines.

“People might have existing antibodies to certain antigens of S. aureus, but the fact that the existing repertoire could actively inhibit a protective response to me was quite surprising,” said Dane Parker, an immunologist and microbiologist at Rutgers New Jersey Medical School who was not involved in the study. “[This study] could potentially shape how people do these types of studies moving forward,” Parker stated.

Liu is optimistic that this work will help scientists develop effective vaccines against S. aureus or challenging diseases, such as malaria or tuberculosis. “We are hoping that folks would also explore in their own systems or their own [chosen] pathogens whether this type of immune evasion mechanism could be at work,” Liu said.


  1. Wertheim HF, et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005;5(12):751-762.
  2. Howden BP, et al. Staphylococcus aureus host interactions and adaptation. Nat Rev Microbiol. 2023;21(6):380-395.
  3. Turner NA, et al. Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research. Nat Rev Microbiol. 2019;17(4):203-218.
  4. Caldera JR, et al. The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches. Cell Rep Med. 2024;5(1).
  5. Lebon A, et al. Dynamics and determinants of Staphylococcus aureus carriage in infancy: The Generation R Study. J Clin Microbiol. 2008;46(10):3517-3521.
  6. Tsai CM, et al. Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine. Cell Host Microbe. 2022;30(8):1163-1172.e6.
  7. Francis T. On the doctrine of original antigenic sin. Proc Am Philos Soc. 1960;104(6):572-578.