Summary Infections frequently contain multiple strains (genotypes) of the same pathogen, yet they are still usually treated as uniform entities. In this Review, we discuss problems with inconsistent definition of the term "strain" and review the prevalence and implications of multiple-strain infections. Up to now, multiple-strain infections have been shown unambiguously in 51 human pathogens (and 21 non-human ones) and are likely to arise in most pathogen species. In human pathogens, multiple-strain infections usually reach considerable frequencies (median 11·3%, mean 21·7% of infections), which are certainly underestimated in many cases because of technical limitations of detection. For many diseases, the importance of multiple-strain infections is still unclear, but theoretical work and experimental results from animal models suggest a broad range of clinically relevant effects. Multiple-strain infections can affect host immune responses and our ability to prevent and treat infection efficiently. Competition and mutualism between strains change pathogen and disease dynamics and promote pathogen evolution. Co-infection enables gene transfer among strains. Taking multiple-strain infections into account will improve our understanding of host-pathogen interactions and disease dynamics, and will provide a basis for novel control approaches.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(11)70241-9.pdf

Prevalence and implications of multiple-strain infections

In apparent contrast to its invasive potential Staphylococcus aureus colonises the anterior nares of 20-80% of the human population. The relationship between host and microbe appears particularly individualised and colonisation status seems somehow predetermined. After decolonisation, persistent carriers often become re-colonised with their prior S. aureus strain, whereas non-carriers resist experimental colonisation. Efforts to identify factors facilitating colonisation have thus far largely focussed on the microorganism rather than on the human host. The host responds to S. aureus nasal colonisation via local expression of antimicrobial peptides, lipids and cytokines. Interplay with the co-existing microbiota also influences colonisation and immune regulation. Transient or persistent S. aureus colonisation induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonisation. Intriguingly, colonised patients who develop bacteraemia may have a lower S. aureus-attributable mortality than their non-colonised counterparts. This could imply a staphylococcal-specific immune ‘priming’ or immunomodulation occurring as a consequence of colonisation and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonisation on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonisation status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonisation and its modulation of host immunity.

/pdf/staphylococcus-aureus-colonization-modulation-of-host-immune-oz8kcy9t1t.pdf

Staphylococcus aureus colonization: modulation of host immune response and impact on human vaccine design

Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus often colonize the nasopharynx. Children are susceptible to bacterial infections during or soon after upper respiratory tract infection (URI). We describe colonization with these 4 bacteria species alone or in combination during URI. Data were from a prospective cohort of healthy children 6 to 36 months of age followed up for 1 year. Analyses of 968 swabs from 212 children indicated that S. pneumoniae colonization is negatively associated with colonization by H. influenzae. Competitive interactions shifted when H. influenzae and M. catarrhalis colonized together. In this situation, the likelihood of colonization with all 3 species is higher. Negative associations were identified between S. pneumoniae and S. aureus and between H. influenzae and S. aureus. Polymicrobial interactions differed by number and species of bacteria present. Antimicrobial therapy and vaccination strategies targeting specific bacterial species may alter the flora in unforeseen ways.

/pdf/microbial-interactions-during-upper-respiratory-tract-4mrzdwl9d1.pdf

Microbial Interactions during Upper Respiratory Tract Infections

The introduction of the conjugate seven-valent pneumococcal vaccine has led to the replacement of vaccine serotypes with nonvaccine serotypes of Streptococcus pneumoniae. This observation implies that intraspecies competition between pneumococci occurs during nasopharyngeal colonization, allowing one strain or set of strains to predominate over others. We investigated the contribution of the blp locus, encoding putative bacteriocins and cognate immunity peptides, to intraspecies competition. We sequenced the relevant regions of the blp locus of a type 6A strain able to inhibit the growth of the type 4 strain, TIGR4, in vitro. Using deletional analysis, we confirmed that inhibitory activity is regulated by the function of the response regulator, BlpR, and requires the two putative bacteriocin genes blpM and blpN. Comparison of the TIGR4 BlpM and -N amino acid sequences demonstrated that only five amino acid differences were sufficient to target the heterologous strain. Analysis of a number of clinical isolates suggested that the BlpMN bacteriocins divide into two families. A mutant in the blpMN operon created in the clinically relevant type 19A background was deficient in both bacteriocin activity and immunity. This strain was unable to compete with both its parent strain and a serotype 4 isolate during cocolonization in the mouse nasopharynx, suggesting that the locus is functional in vivo and confirming its role in promoting intraspecies competition.

https://iai.asm.org/content/iai/75/1/443.full.pdf

The blp Bacteriocins of Streptococcus pneumoniae Mediate Intraspecies Competition both In Vitro and In Vivo

Although there is tremendous interest in understanding the evolutionary roles of horizontal gene transfer (HGT) processes that occur during chronic polyclonal infections, to date there have been few studies that directly address this topic. We have characterized multiple HGT events that most likely occurred during polyclonal infection among nasopharyngeal strains of Streptococcus pneumoniae recovered from a child suffering from chronic upper respiratory and middle-ear infections. Whole genome sequencing and comparative genomics were performed on six isolates collected during symptomatic episodes over a period of seven months. From these comparisons we determined that five of the isolates were genetically highly similar and likely represented a dominant lineage. We analyzed all genic and allelic differences among all six isolates and found that all differences tended to occur within contiguous genomic blocks, suggestive of strain evolution by homologous recombination. From these analyses we identified three strains (two of which were recovered on two different occasions) that appear to have been derived sequentially, one from the next, each by multiple recombination events. We also identified a fourth strain that contains many of the genomic segments that differentiate the three highly related strains from one another, and have hypothesized that this fourth strain may have served as a donor multiple times in the evolution of the dominant strain line. The variations among the parent, daughter, and grand-daughter recombinant strains collectively cover greater than seven percent of the genome and are grouped into 23 chromosomal clusters. While capturing in vivo HGT, these data support the distributed genome hypothesis and suggest that a single competence event in pneumococci can result in the replacement of DNA at multiple non-adjacent loci.

/pdf/generation-of-genic-diversity-among-streptococcus-pneumoniae-1mbvvep4js.pdf

Generation of Genic Diversity among Streptococcus pneumoniae Strains via Horizontal Gene Transfer during a Chronic Polyclonal Pediatric Infection

Background Declining antimicrobial susceptibility to current gonorrhoea antibiotic treatment and inadequate treatment options have raised the possibility of untreatable gonorrhoea. New prevention approaches, such as vaccination, are needed. Outer membrane vesicle meningococcal serogroup B vaccines might be protective against gonorrhoea. We evaluated the effectiveness of a serogroup B meningococcal outer membrane vesicle vaccine (MenB-4C) against gonorrhoea in individuals aged 16–23 years in two US cities. Methods We identified laboratory-confirmed gonorrhoea and chlamydia infections among individuals aged 16–23 years from sexually transmitted infection surveillance records in New York City and Philadelphia from 2016 to 2018. We linked gonorrhoea and chlamydia case records to immunisation registry records to determine MenB-4C vaccination status at infection, defined as complete vaccination (two MenB-4C doses administered 30–180 days apart), partial vaccination (single MenB-4C vaccine dose), or no vaccination (serogroup B meningococcal vaccine naive). Using log-binomial regression with generalised estimating equations to account for correlations between multiple infections per patient, we calculated adjusted prevalence ratios (APR) and 95% CIs to determine if vaccination was protective against gonorrhoea. We used individual-level data for descriptive analyses and infection-level data for regression analyses. Findings Between Jan 1, 2016, and Dec 31, 2018, we identified 167 706 infections (18 099 gonococcal infections, 124 876 chlamydial infections, and 24 731 gonococcal and chlamydial co-infections) among 109 737 individuals linked to the immunisation registries. 7692 individuals were vaccinated, of whom 4032 (52·4%) had received one dose, 3596 (46·7%) two doses, and 64 (<1·0%) at least three doses. Compared with no vaccination, complete vaccination series (APR 0·60, 95% CI 0·47–0·77; p<0·0001) and partial vaccination series (0·74, 0·63–0·88; p=0·0012) were protective against gonorrhoea. Complete MenB-4C vaccination series was 40% (95% CI 23–53) effective against gonorrhoea and partial MenB-4C vaccination series was 26% (12–37) effective. Interpretation MenB-4C vaccination was associated with a reduced gonorrhoea prevalence. MenB-4C could offer cross-protection against Neisseria gonorrhoeae. Development of an effective gonococcal vaccine might be feasible with implications for gonorrhoea prevention and control. Funding None. Declining antimicrobial susceptibility to current gonorrhoea antibiotic treatment and inadequate treatment options have raised the possibility of untreatable gonorrhoea. New prevention approaches, such as vaccination, are needed. Outer membrane vesicle meningococcal serogroup B vaccines might be protective against gonorrhoea. We evaluated the effectiveness of a serogroup B meningococcal outer membrane vesicle vaccine (MenB-4C) against gonorrhoea in individuals aged 16–23 years in two US cities. We identified laboratory-confirmed gonorrhoea and chlamydia infections among individuals aged 16–23 years from sexually transmitted infection surveillance records in New York City and Philadelphia from 2016 to 2018. We linked gonorrhoea and chlamydia case records to immunisation registry records to determine MenB-4C vaccination status at infection, defined as complete vaccination (two MenB-4C doses administered 30–180 days apart), partial vaccination (single MenB-4C vaccine dose), or no vaccination (serogroup B meningococcal vaccine naive). Using log-binomial regression with generalised estimating equations to account for correlations between multiple infections per patient, we calculated adjusted prevalence ratios (APR) and 95% CIs to determine if vaccination was protective against gonorrhoea. We used individual-level data for descriptive analyses and infection-level data for regression analyses. Between Jan 1, 2016, and Dec 31, 2018, we identified 167 706 infections (18 099 gonococcal infections, 124 876 chlamydial infections, and 24 731 gonococcal and chlamydial co-infections) among 109 737 individuals linked to the immunisation registries. 7692 individuals were vaccinated, of whom 4032 (52·4%) had received one dose, 3596 (46·7%) two doses, and 64 (<1·0%) at least three doses. Compared with no vaccination, complete vaccination series (APR 0·60, 95% CI 0·47–0·77; p<0·0001) and partial vaccination series (0·74, 0·63–0·88; p=0·0012) were protective against gonorrhoea. Complete MenB-4C vaccination series was 40% (95% CI 23–53) effective against gonorrhoea and partial MenB-4C vaccination series was 26% (12–37) effective. MenB-4C vaccination was associated with a reduced gonorrhoea prevalence. MenB-4C could offer cross-protection against Neisseria gonorrhoeae. Development of an effective gonococcal vaccine might be feasible with implications for gonorrhoea prevention and control. 

Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.

BACKGROUND
Health departments prioritize reproductive-aged women for syphilis partner services (PS) to prevent congenital syphilis (CS). We assessed trends in PS effectiveness among women.


METHODS
We classified reported syphilis cases (all stages) between 2015-2022 from eight US jurisdictions as non-pregnant women (NPW) >45 years ("non-reproductive-aged NPW", a group sometimes not assigned for PS), NPW between 15-45 years ("reproductive-aged NPW"), pregnant women without a CS outcome ("pregnant no CS"), and pregnant women with a CS outcome ("pregnant and CS"). We compared trends in the yearly proportion within each group who reported partners and whose partners were treated (preventatively or if infected, before or due to PS).


RESULTS
During 2015-2022, annual counts of syphilis increased (non-reproductive-aged NPW +151.5%; reproductive-aged NPW +208.0%; pregnant no CS +160.4%; pregnant and CS +559.3%). Overall, 88% of women were assigned for PS, >90% of assigned cases were interviewed and > 94% of interviewed cases were treated. Across groups, the proportion interviewed naming ≥1 locatable partner was higher in 2015 compared to 2022 (non-reproductive-aged NPW 53.3% to 36.3%; reproductive-aged NPW 68.6% to 42.8%; pregnant no CS 80.8% to 65.0%; pregnant and CS 73.6% to 47.0%), and the proportion with ≥1 partner treated was higher(non-reproductive-aged NPW 31.3% to 21.7%; reproductive-aged NPW 43.7% to 24.9%; pregnant no CS 53.0% to 38.0%; pregnant and CS 41.5% to 23.4%).


CONCLUSION
As syphilis increased, health departments reached most women with syphilis and assured treatment. A decreasing proportion of women reported locatable partners. Integration of PS with other strategies is needed to prevent re-infection and syphilis transmission in women.

Trends in Syphilis Partner Services Outcomes among Women in 8 US Jurisdictions, 2015-2022.

Healthy vaccinee bias likely did not confound earlier studies demonstrating the protective effect of outer-membrane vesicle serogroup B meningococcal vaccines against gonorrhea. Abstract Observational studies demonstrated 30% to 40% effectiveness of outer-membrane vesicle (OMV) meningococcal serogroup B vaccines against gonorrhea. To explore whether healthy vaccinee bias influenced such findings, we examined the effectiveness of MenB-FHbp, a non-OMV vaccine that is not protective against gonorrhea. MenB-FHbp was ineffective against gonorrhea. Healthy vaccinee bias likely did not confound earlier studies of OMV vaccines.

Healthy Vaccinee Bias and MenB-FHbp Vaccine Effectiveness Against Gonorrhea

We studied genetic diversity in Streptococcus pneumoniae and Haemophilus influenzae in throat culture isolates from 38 children attending two day-care centers in Michigan. Culture specimens were collected weekly; 184 S. pneumoniae and 418 H. influenzae were isolated from the cultures. Pulsed-field gel electrophoresis identified 29 patterns among the S. pneumoniae isolates and 87 among the H. influenzae isolates. Of the cultures, 5% contained multiple genetic types of S. pneumoniae, and 43% contained multiple types of H. influenzae. Carriage of multiple H. influenzae isolates, which was associated with exposure to smoking, history of allergies, and age 36 to 47 months, may increase risk for otitis media in children.

/pdf/risk-factors-for-otitis-media-and-carriage-of-multiple-3l60pva34u.pdf

Risk factors for otitis media and carriage of multiple strains of Haemophilus influenzae and Streptococcus pneumoniae.

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Papers

Effectiveness of a serogroup B outer membrane vesicle meningococcal vaccine against gonorrhoea: a retrospective observational study.

Trends in Syphilis Partner Services Outcomes among Women in 8 US Jurisdictions, 2015-2022.

Healthy Vaccinee Bias and MenB-FHbp Vaccine Effectiveness Against Gonorrhea

Risk factors for otitis media and carriage of multiple strains of Haemophilus influenzae and Streptococcus pneumoniae.