Neurological complications of vaccination with outer surface protein A (OspA) 2011
http://www.ncbi.nlm.nih.gov/pubmed/21673416

6. Conclusions
OspA vaccines are capable of initiating a wide array of acute and chronic neurological AE. Not surprisingly, some of these AE resembled neurological manifestations of Lyme disease, and point to reactivation of latent infection, molecular mimecry or aberrant immune responses as mechanisms. Adverse effect profiles from limited pre-licensure studies should not deter from making a clinical determination of relatedness for seemingly new or unreported AE, This is particularly true if the AE follows along a pattern seen for the disease being vaccinated against.

http://www.medscape.com/viewarticle/710148_3
Human Lyme Disease Vaccines: Past and Future Concerns: Concerns With the OspA Vaccin
Future Microbiology
Dean T. Nardelli, Erik L. Munson, Steven M. Callister, Ronald F. Schell
Future Microbiol. 2009;4(4):457-469.

Potential for Adverse Effects

A paramount concern in the creation of a vaccine is that it does not induce harmful side effects, despite its ability to prevent disease. Indeed, ample evidence in animal models and humans demonstrates that vaccination with OspA provides at least short-term antibody-mediated protection against infection with B. burgdorferi. However, studies in animals and humans conducted prior to and after the Phase III OspA human vaccine trials showed that the immune response to OspA may come with the caveat of autoreactivity against the recipient. Recently, Steere and Glickstein hypothesized that structural homology between host peptides and OspA induces an autoimmune mechanism, which mediates antibiotic treatment-resistant Lyme arthritis.[64] In addition, reports of Lyme disease symptoms[65,66] in recipients of OspA vaccines raised questions about the safety of such a vaccine. Concerns about these potential side effects may have played a factor in the withdrawal of the Lyme disease vaccine from the market.

Although the humoral response to OspA appears to be effective in the clearance of B. burgdorferi infection, several studies have linked the development of OspA-specific antibodies to the manifestation of late-stage Lyme disease symptoms - particularly chronic arthritis. Steere et al. demonstrated a genetic predisposition to the development of chronic, antibiotic treatment-resistant Lyme arthritis.[67] A vast majority of patients with chronic arthritis were shown to possess either, or both, human leukocyte antigen (HLA)-DR4 or -DR2 alleles, whereas individuals with short- or moderate-duration arthritis were less likely to possess these alleles.[67] The onset of prolonged bouts of arthritis in HLA-DR4-positive individuals coincided with development of strong IgG responses to OspA months to years after manifestation of initial Lyme disease symptoms.[68] In addition, most patients with chronic arthritis developed a strong IgG response to a C-terminal OspA epitope, and this anti-OspA antibody response reflected the duration of arthritis.[58] These findings were supported by Akin et al., who showed that the production of anti-OspA IgG antibodies correlated with the duration and severity of chronic Lyme arthritis, while the IgG responses to most other B. burgdorferi proteins were indicative of early-stage disease manifestations.[69] These studies indicate that the development of chronic Lyme arthritis is related to immune recognition of OspA months after the onset of initial disease symptoms. The correlation between late-stage OspA reactivity and arthritis development suggests epitopes of OspA may induce an adverse response in humans.

This assertion is supported by the association of OspA-reactive T cells in the development of chronic Lyme arthritis. The T-cell response to B. burgdorferi polypeptides in patients with chronic Lyme arthritis was stronger than that of infected patients with transient arthritis,[70] and T-cell clones derived from patients with Lyme arthritis were shown to bind to OspA epitopes.[71-73] In addition, T cells from the synovial fluid or peripheral blood of patients with antibiotic treatment-resistant Lyme arthritis were able to preferentially recognize OspA, whereas those of individuals with treatment-responsive arthritis were not.[74] OspA-reactive T cells localized in the joints of patients with chronic Lyme arthritis were subsequently identified as Th1 cells.[75] However, despite an abundance of circumstantial evidence for OspA-induced T-cell autoreactivity in the development of chronic Lyme arthritis, a host peptide with homology to any borrelial antigen had yet to be indentified.

Various HLA-DRB alleles associated with rheumatoid arthritis[76] are frequently found in individuals with Lyme arthritis several years after receiving antibiotic treatment.[77,78] Using a transgenic mouse model expressing a human major histocompatibility complex class II HLA-DRB allele, an immunodominant OspA epitope (OspA165-173) was identified.[79] The structure of this OspA epitope was shown to be homologous to a sequence of human leukocyte function-associated antigen-1 (hLFA-1),[79] providing the first evidence for possible autoimmune-inducing molecular mimicry between borrelial and human peptides. Subsequently, certain HLA-DRB molecules of the DR4 subtype were shown to bind OspA165-173 and its hLFA-1 homolog,[77] and an association between OspA165-173-binding HLA-DR molecules and antibiotic treatment-resistant Lyme arthritis was postulated.[78] By contrast, LFA-1 was shown to be a weak agonist for T cells reactive against OspA165-173, making it an unlikely source of autoimmune-inducing molecular mimicry.[80] Nonetheless, the hypothesis of arthritis-inducing molecular mimicry to host tissue is intriguing.[64] In addition, reports of adverse effects in humans after OspA vaccination raise a red flag that OspA is involved in the induction of those effects.[65,66] Moreover, nearly 1000 reports of adverse effects following OspA vaccination were documented by the US FDA less than 2 years after the vaccine was placed on the market.[81] Although most of these cases were not reported as published case studies, these events of adverse effects contributed to the withdrawal of the vaccine for use in humans.

In addition, the idea that vaccination with B. burgdorferi or its components may carry the risk of direct or indirect arthritic side effects was known prior to the FDA-approved human OspA vaccine field trials. Lim et al. showed that hamsters vaccinated with whole Borrelia organisms developed a severe, destructive osteoarthropathy following infection with a heterologous borrelial strain.[82] Arthritis in these vaccinated hamsters was mediated by Borrelia-specific T cells.[83] In addition, severe, destructive arthritis developed following heterologous infection of Borrelia-vaccinated mice.[84-87] Most importantly, Croke et al. showed that vaccination with recombinant OspA also primed animals for arthritis development following heterologous challenge.[88] In addition, OspA vaccination has also been linked to development of arthritis and neurological disease in humans.[65-66] Collectively, these findings represent various lines of evidence of OspA-induced adverse effects in animals and humans. Interestingly, these adverse effects were ignored since they may not have reflected the preliminary safety data collected in humans by Keller et al.[38] These adverse reports highlight the necessity for evaluating all evidence on the safety of prospective Lyme vaccines, particularly those composed of OspA.

New approaches for creating safe and effective OspA vaccines for Lyme disease are in development. A modified OspA-based vaccine showed potential for protection against infection without induction of autoreactive T cells.[89] An epitope on OspA is reportedly able to induce autoreactive T cells owing to its significant structural homology to that of hLFA-1.[79] These investigators mutated the potentially cross-reactive OspA epitope while maintaining the structure of an epitope reported to bind protective antibodies.[89] Mice vaccinated with the modified OspA were protected from needle challenge with B. burgdorferi, while OspA-reactive human T cells did not respond to the mutated OspA protein.[89] Although more work is required to characterize the vaccine-induced immune response and protection afforded against tick-borne infection, removal of this potentially autoreactive epitope may be a key requirement for any future Lyme disease vaccine containing OspA. However, this vaccine still does not overcome the fact that OspA is downregulated in the feeding tick.

Lyme nephritis, Meryl P. Littman VMD, DACVIM
Journal of Veterinary Emergency and Critical Care
Volume 23, Issue 2, <http://onlinelibrary.wiley.com/doi/10.1111/vec.2013.23.issue-2/issuetoc> pages 163–173, March/April 2013
http://onlinelibrary.wiley.com/doi/10.1111/vec.12026/abstract

(LN=Lyme nephritis, CIC - circulating immune complexes)


" Vaccination for LN, a disease with an immune-mediated pathogenesis, may be problematic and is still controversial even in endemic areas. Tick control is needed to prevent other diseases; 95% of Lyme+ dogs remain asymptomatic; Lyme arthritis in the <5% responds quickly to safe, inexpensive antimicrobials; the duration of immunity requires frequent boostering and is not 100%; Lyme bacterin has been associated with more postvaccinal adverse events than other vaccines we use; and there are concerns about possible immune-mediated sequellae in genetically predisposed dogs. Since this most serious form of Lyme disease affecting <2% of Lyme+ dogs is caused by immune-complex disease, and since high CIC occur for weeks to months after vaccination (longer in boostered or Lyme+ dogs, and longer with bacterin than subunit ospA vaccine), it is theoretically possible that vaccinal immune-complexes could be deposited in glomeruli of a genetically predisposed individual. Potentially, this could happen over time and not appear temporally related to vaccination. Without an inducible experimental model, it is difficult to determine the host-pathogen factors that are associated with LN and whether vaccine antigens protect against it, or if they could sensitize or aggravate the condition. Early reports showed up to 30% of LN suspects had been vaccinated; 6 dogs had been vaccinated with Lyme bacterin 2 weeks to 15 months prior to presentation with LN.

OspA is in all currently available vaccines and is proinflammatory enough that it does not require an adjuvant. OspA has been associated with immune-mediated disease in other species including people with nonresponsive Lyme arthritis. Monoclonal anti-ospA stains showed positive staining in kidneys of dogs with LN. In hamsters, Lyme bacterin or subunit ospA vaccine caused more severe arthritis in vaccinates than in nonvaccinates after challenge. OspA alone is arthritogenic in rats; sensitization occurs so that even more intense arthritis is seen with boosters. Many doses of Lyme vaccines have been used and most dogs do not get sick, but most dogs do not get sick with Lyme disease either."

Two Missouri farmers have been infected with a brand-new tick-borne virus that the Centers for Disease Control and Prevention is calling the Heartland virus.

The men recovered but suffered serious illness that required hospital care and weeks of convalescence. Symptoms included fever, severe fatigue, headache and nausea. Their platelet counts plummeted, but even though platelets are necessary for blood clotting, the men didn't suffer abnormal bleeding....

...the new virus is in the phlebovirus family, which contains more than 70 members. And here's another twist: Heartland virus appears to be a cousin of another new human virus called severe fever with thrombocytopenia syndrome virus, discovered last year in China. Another possible cousin may be Bhanja virus, a little-studied virus that has been found in some mammals, birds and reptiles in Asia, Africa and Europe.