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Current knowledge on immune cell interactions with Borrelia burgdorferi (Bb) derives mostly from studies done in vitro and ex vivo, which cannot assess host immunity to natural tick-delivered Bb within the complex architecture of host tissues. We report the first in vivo study on local and systemic immune responses to Bb during tick feeding on a surrogate reservoir host, in comparison with uninfected-tick and subcutaneously delivered Bb. We show that uninfected-tick and tick-transmitted Bb engaged mixed type-1/type-2/type-17 immune responses in the presence of anti-inflammatory IL-10, in contrast to a type-1 response induced by subcutaneously delivered Bb. Analyses of immune responses to tick-transmitted Bb in a reservoir host can enlighten immunity mechanisms that mediate persistence of Bb.

Testing for IgM antibodies to Borrelia burgdorferi in Scottish patients with suspected Lyme borreliosis was introduced in 2018 to supplement the IgG testing already in situ. Results from 2018 to 2020 were assessed alongside available clinical data to evaluate the utility of IgM testing in serum. An estimated false positive rate of 25.5% was observed with IgM immunoblot vs 80.1% for IgM chemiluminescent immunoassay (CLIA). IgM testing can aid earlier diagnoses if used within a selective two-tier testing protocol: only patients with acute onset of symptoms should be tested for IgM CLIA but confirmation by immunoblot and consideration of clinical picture is necessary.

Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes scapularis ticks, remains a significant vector-borne illness in the United States. Small mammal reservoirs, particularly Peromyscus leucopus, play a critical role in B. burgdorferi maintenance. Here, we conducted a five-year, randomized, double-blinded, placebo-controlled field trial deploying an oral OspA-based reservoir-targeted vaccine (RTV) across seven Maryland sites. Bayesian modeling provided estimates of vaccine impact on mouse anti-OspA antibody levels, nymphal tick infection prevalence (NIP), mouse infection rates, and seroconversion to B. burgdorferi in hunting dogs. RTV sites exhibited an estimated 10.5% proportional increase in protective murine anti-OspA antibody levels and a 15.4% reduction in NIP by year five. We also found a lower infection prevalence in mouse blood-fed nymphal ticks (9.8%). RTV sites exhibited modest decreases in mouse infection prevalence, and dog seroconversion rates were similar between groups. Our results indicate that anti-OspA antibody in vaccinated-infected/uninfected P. leucopus reduced B. burgdorferi summertime larval infection prevalence, measured as NIP reductions the following spring. This suggests that OspA-based oral RTV reduces B. burgdorferi transstadial transmission within tick populations. Our findings advance the development of reservoir-targeted solutions for Lyme disease prevention. Further evaluation of impacts on incidental hosts is needed.

UK laboratory diagnosis of Lyme disease involves the Standard Two-Tier serological approach. The negative predictive value of the test has been challenged, particularly in the early stages of disease. In order to better understand the host response to Lyme disease and to identify any potential host biomarkers that may correlate with early infection, proteomic and transcriptomic analyses were undertaken on Lyme disease patient samples. Label free quantitative spectrometry was used to measure and compare the serum proteome of seropositive patients against that of individuals that had tested seronegative for Lyme disease and a control group consisting of samples from normal healthy donors and patients with related infectious disease including leptospirosis and syphilis. Seropositive and seronegative individuals were found to be remarkably similar at the serum proteome level. Of the 12 proteins found to be at significantly different abundance between groups, the protein Lipocalin-2 was of particular interest due to role its role modulation of immune responses. Further analysis by ELISA in additional samples showed that Lipocalin-2 was significantly increased in Lyme disease positive patients when compared to normal healthy donors.Whole blood samples from patients with Lyme disease were then RNA sequenced and differential gene analysis was performed using sequencing data for healthy controls. Several pathways associated with bacterial immune response in the host were identified, together with actin rearrangement and oxidative stress pathways. eIF2 signalling was found to be significantly reduced in patients with early Lyme disease. The pathway has previously been identified as being down regulated during Lyme disease. In later samples from patients, following antibiotic therapy, eIF2 signalling levels were found to increase back towards those seen in control samples from normal/healthy individuals.

The efficacy and duration of passive immunity protection depends on maternal antibody levels and transfer efficiency. We investigated whether oral vaccination of dams with recombinant OspA-expressing could induce maternal transfer of anti-OspA antibodies and protect pups from challenge. Dams were vaccinated until breeding pairs were created (i), until parturition (ii), and until pups were 2 weeks old (iii). Pups were challenged with nymphal -transmitted at ∼ 4 weeks of age. Anti-OspA IgG were quantified in dams and pups, and anti IgG were quantified in pups. burden was assessed by qPCR in pups' tissues ∼ 4 weeks after tick challenge and viability of was assessed by culture of heart tissue. pups born to dams vaccinated until breeding had low serologic anti-OspA antibody and were not protected from tick transmitted infection. However, when dams' vaccination extended until parturition and until pups were two weeks old, significant anti-OspA antibody transfer and protection from infection occurred. This was evidenced by absence of antibody to PepVF, absence of DNA in heart and bladder tissues, and absence of in culture from heart tissues from pups euthanized >9 weeks after birth. We show that transfer of anti-OspA antibodies from vaccinated dams to offspring prevents tick transmission and infection dynamics of in the major reservoir host of this spirochete in the United States. This study contributes to our understanding of how interventions based in reservoir targeted OspA vaccines designed to block transmission of from infected ticks may disrupt the enzootic cycle of this spirochete and reduce incidence of Lyme disease.

Maternal antibody transfer provides passive immunity to offspring; however, the efficacy and duration of this protection depends on maternal antibody levels and transfer efficiency. We investigated whether oral vaccination of Peromyscus leucopus dams with recombinant OspA-expressing E. coli could induce maternal transfer of anti-OspA antibodies and protect pups from Borrelia burgdorferi challenge. Dams were vaccinated for different durations: (i) until breeding, (ii) until birth of pups, or (iii) until pups were 2 weeks old. Pups were challenged with Ixodes scapularis nymph-transmitted B. burgdorferi at ~ 4 weeks of age. Anti-OspA IgG were quantified in dams and pups, and B. burgdorferi anti-PepVF IgG were quantified in pups. Furthermore, B. burgdorferi burden was assessed by qPCR targeting the flaB gene in pups’ heart and bladder tissues > 4 weeks after tick challenge. P. leucopus pups born to dams vaccinated until breeding, exhibited low anti-OspA antibody and were not protected from tick transmitted B. burgdorferi infection. However, when maternal vaccination extended until pups were born and until pups were two weeks old, significant anti-OspA antibody transfer and protection occurred. This was evidenced by absence of antibody to B. burgdorferi PepVF, absence of B. burgdorferi flaB DNA in heart and bladder tissues, and absence of flaB in culture from heart tissues from pups euthanized >9 weeks after birth. We show that transfer of anti-OspA antibodies from P. leucopus dams to offspring prevents tick transmission of B. burgdorferi in the major reservoir host of this spirochete in the United States.

Vaccines targeting outer surface protein A (OspA) of protect against Lyme disease by inducing antibodies in the host that neutralize spirochetes in the tick midgut during engorgement before transmission occurs. We evaluated whether heterologous vaccination enhances protection compared to homologous delivery of the immunogen. C3H-HeN mice were immunized with a parainfluenza virus 5 vector (PIV5) containing a modified OspA protein (OspA ) using three prime-boost immunization regimens: homologous PIV5 intranasal/intranasal (IN/IN), homologous rOspA (protein) subcutaneous/subcutaneous (SC/SC), or heterologous intranasal PIV5-A /subcutaneous rOspA (IN/SC). Immunized mice were then challenged with nymphal ticks infected with 19 strains of three months post-prime vaccination. Three weeks after the last day of tick challenge, blood and tissues were collected from euthanized mice. All OspA-containing regimens elicited strong systemic IgG antibody responses that exceeded established protective thresholds. Vaccination markedly reduced loads in engorged nymphal ticks. Homologous IN/IN and SC/SC regimens produced the lowest geometric mean burdens in nymphs (2.6 × 10 and 1.8 × 10 copies, respectively), corresponding to ~1.8-2.0 log reductions relative to controls; the heterologous IN/SC regimen produced a more modest reduction (~1.7 log ; p = 0.0071 vs IN/IN, p = 0.0003 vs SC/SC). Across all vaccinated groups, no systemic infection with was observed as evidenced by absence of motile spirochetes in cultures from tissues, although one mouse (1/9, 11%) in the heterologous IN/SC regimen, had evidence of increased pepVF seroconversion and low-level DNA in culture. Thus, homologous regimens yielded more consistent protective immunity with absent of signs of dissemination, suggesting that high systemic anti-OspA IgG antibody titers, rather than alternate immunization routes, were associated with the most consistent protection outcomes. PIV5-A is a promising vaccine candidate for development of next-generation homologous or heterologous human Lyme disease vaccines.

Lyme disease, caused by and transmitted by ticks, remains a significant vector-borne illness in the United States. Small mammal reservoirs, particularly , play a critical role in maintenance. Here we conducted a five-year, randomized, double-blinded, placebo-controlled field trial deploying an oral OspA-based reservoir targeted vaccine (RTV) across seven Maryland sites. Bayesian modeling provided estimates of vaccine impact on mouse anti-OspA antibody levels, nymphal tick infection prevalence (NIP), mouse infection rates, and seroconversion to in hunting dogs. RTV sites exhibited an estimated 10.5% proportional increase in protective murine anti-OspA antibody levels and a 15.4% reduction in NIP by year five. We also found a lower infection prevalence in mouse blood fed nymphal ticks (9.8%). RTV sites exhibited modest decreases in mouse infection prevalence and dog seroconversion rates were similar between groups. Our results indicate that anti-OspA antibody in vaccinated-infected reduced summertime larval infection prevalence, measured as NIP reductions the following spring. This suggests that OspA-based oral RTV reduces transstadial transmission within tick populations. Our findings advance development of reservoir targeted solutions for Lyme disease prevention. Further evaluation of impacts on incidental hosts is needed.