A brief history of OspA vaccines including their impact on diagnostic testing for Lyme disease.

The only United States Food and Drug Administration approved vaccine preparation to prevent Lyme disease consisted of a single recombinant outer surface protein A (OspA), which was marketed for use from late 1998 until early 2002, with no vaccine currently available for humans for nearly 20 years. OspA vaccines generate an antibody-mediated, transmission blocking immunity, that prevents Borrelia burgdorferi from being transmitted during a tick bite. Although this OspA vaccine was safe and effective, it likely would have required booster doses to maintain immunity, and vaccination regularly caused false positive results on first-tier serologic testing for Lyme disease, when a whole cell-based enzyme immunoassay was used. Clinical trials are in progress to test a new multivalent OspA vaccine designed to prevent Lyme disease in both the United States and Europe.

A systematic review and meta-analysis for the adverse effects, immunogenicity and efficacy of Lyme disease vaccines: Guiding novel vaccine development.

BACKGROUND: Lyme borreliosis (LB) is the most prevalent arthropod-borne infectious disease in North America. Currently, no vaccine is available to prevent LB in humans, although monovalent and multivalent vaccines have been developed in the past. OBJECTIVE: The aim of the current study is to conduct a systematic review and meta-analysis to evaluate and compare the findings from these two classes of vaccines for their reactogenicity, immunogenicity and efficacy, in the hope this may assist in the development of future vaccines. METHODS: A search strategy was developed for online databases (PubMed, Ovid MEDLINE, and Embase). Search terms used were "vaccine/vaccination", "Lyme disease/Borreliosis", "clinical trial(s)" and "efficacy". Only seven clinical trials were included to compare the results of the monovalent vaccines to those of the multivalent one. Meta-analyses were conducted to evaluate the reactogenicity and immunogenicity of the two vaccine classes. Odds ratio (OR) for LB (and 95% confidence intervals; 95% CI) were calculated for the efficacy of the monovalent vaccine from three different clinical trials at different dose schedules. RESULTS: Incidence of redness (local adverse effect) and fever (systemic side effect) were, respectively, 6.8- and 2.9-fold significantly lower (p < 0.05) in individuals who received multivalent vaccines compared to those receiving the monovalent one. Incidences of all other local and systemic adverse effects were non-significantly lower in the multivalent vaccine compared to the monovalent vaccines. Seroprotection was comparable among individuals who received the two vaccine classes at the 30 µg dose level. Efficacy in the prevention of LB was only evaluated for the monovalent vaccines. OR of LB ranged from 0.49 (95% CI: 0.14-0.70; p < 0.005, vs. placebo) to 0.31 (95% CI: 0.26-0.63; p < 0.005) for the initial and final doses respectively, with an overall OR of 0.4 (95% CI: 0.26-0.63, p < 0.001). CONCLUSION: The current study further validates that the monovalent and multivalent LB vaccines result in mild local side effects and self-limiting systemic adverse effects, with the multivalent vaccine slightly more tolerable than the monovalent one. Both vaccine classes were similarly highly immunogenic. A new vaccine with high safety standards, better efficacy, low cost, and public acceptance is yet to be developed. Meanwhile, personal protection limiting exposure to ticks is recommended.

Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics.

Lyme borreliosis (LB) is a multisystem infectious disease with a growing burden in many parts of North America, Asia and Europe. Persistent infection of LB can usually be treated effectively with antibiotic therapy, but it may be followed by post-treatment Lyme disease syndrome. Therefore, it is important to begin with treatment in the early phase of the disease. Vaccination shows potential as the most effective way of preventing LB and reducing its burden in these continents. It is concluded that there is a need for continuous effort in research from all perspectives on LB, especially regarding prevention with novel vaccines, their development, clinical efficacy and cost-effectiveness. This review may help to further develop (cost-) effective strategies for prevention and control of the disease to reduce its burden and achieve population-wide health benefits.

Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial.

BACKGROUND: Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non-adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults. METHODS: Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18-70 years who were seronegative for B. burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 µg, 60 µg, or 90 µg OspA antigen with or without an adjuvant, with intervals of 28 days, and a booster 9-12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1-6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347. FINDINGS: 300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 µg, 51 to 60 µg, and 50 to 90 µg doses), and 149 to non-adjuvanted vaccines (50 to 30 µg, 49 to 60 µg, and 50 to 90 µg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions (risk ratio 0·54 [95% CI 0·41-0·70]; p<0·0001) and of moderate or severe systemic reactions (0·35 [0·13-0·92]; p=0·034) was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 µg adjuvanted formulation had the best tolerability profile; only headache (five [10%, 95% CI 4-20] of 50), injection-site pain (16 [32%, 21-45]), and tenderness (17 [34%, 23-47]) affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1-6 after the first three vaccinations (range 6944-17,321) and booster (19,056-32,824) immunisations. The 30 µg adjuvanted formulation induced the highest antibody titres after the booster: range 26,143 (95% CI 18,906-36,151) to 42,381 (31,288-57,407). INTERPRETATION: The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin. FUNDING: Baxter.

The rise and fall of the lyme disease vaccines: a cautionary tale for risk interventions in American medicine and public health.

CONTEXT: Two vaccines to prevent Lyme disease (LD) were developed and tested in the 1990s. Despite evidence of their safety and efficacy in clinical trials and initial postmarketing surveillance, one vaccine was withdrawn before the regulatory review and the other after only three years on the market. An investigation of their history can illuminate (1) the challenges faced by many new risk-reducing products and practices and (2) the important role played by their social and psychological, as distinct from their biomedical or scientific, efficacy in how they are used, and their ultimate market success or failure. METHODS: This article reviewed medical and popular literature on LD vaccines, analyzed the regulatory hearings, and conducted interviews with key participants. FINDINGS: Even if proved safe and effective, LD vaccines faced regulatory and market challenges because the disease was geographically limited, treatable, and preventable by other means. Pharmaceutical companies nevertheless hoped to appeal to consumers' desire for protection and control and to their widespread fear of the disease. The LD advocacy community initially supported the vaccines but soon became critical opponents. The vaccines' success was seen as threatening their central position that LD was chronic, protean, and difficult to treat. The activists' opposition flipped the vaccines' social and psychological efficacy. Instead of the vaccines restoring control and reducing fear, demand was undermined by beliefs that the vaccines caused an LD-like syndrome. CONCLUSIONS: The social and psychological efficacy of many risk-reducing practices and products, such as new "personalized vaccines," is to provide insurance and reduce fear. Yet the actions of self-interested actors can easily undermine this appeal. In addition to evaluating the scientific efficacy and safety of these practices and products, policymakers and others need to understand, anticipate, and perhaps shape the potential social and psychological work they might do.

Vaccines against Lyme disease: What happened and what lessons can we learn?

This article reviews events that led to the withdrawal of the only vaccine to prevent Lyme disease licensed in the United States. The primary issues that led to the vaccine's withdrawal appear to be a combination of vaccine safety concerns, sparked by a molecular mimicry hypothesis that suggested that the vaccine antigen, outer surface protein A, serves as an autoantigen and hence was arthritogenic; concerns raised by anti-vaccine groups regarding vaccine safety; vaccine cost; a difficult vaccination schedule and the potential need for boosters; class action lawsuits; uncertainty regarding risk of disease; and low public demand. This article reviews lessons learned from these events and proposes that future candidate Lyme disease vaccines are unlikely to be developed, tested, and used within the United States in the near future, thus leaving at-risk populations unprotected.

Relationship between immunity to Borrelia burgdorferi outer-surface protein A (OspA) and Lyme arthritis.

Antibiotic-refractory Lyme arthritis may result from Borrelia burgdorferi-induced autoimmunity in affected joints. Such patients usually have certain HLA-DRB1 molecules that bind an epitope of B. burgdorferi outer-surface protein A (OspA163₋175), and cellular and humoral immune responses to OspA are greater in patients with antibiotic-refractory arthritis than in those with antibiotic-responsive arthritis. Recent work in a mouse model suggests that, during B. burgdorferi infection, OspA in genetically susceptible individuals stimulates a particularly strong T(H)1 response, which may be one of several factors that can help set the stage for a putative autoimmune response in affected joints. However, vaccination with OspA did not induce arthritis in this mouse model, and case and control comparisons in human vaccine trials did not show an increased frequency of arthritis among OspA-vaccinated individuals. Thus, a vaccine-induced immune response to OspA does not replicate the sequence of events needed in the natural infection to induce antibiotic-refractory Lyme arthritis.

Correcting a public health fiasco: The need for a new vaccine against Lyme disease.

A vaccine against Lyme disease was licensed in the United States in 1998 but was subsequently removed from the market because of lack of sales. I believe that the poor acceptance of the vaccine was based on tepid recommendations by the Centers for Disease Control and Prevention (CDC), undocumented and probably nonexistent safety issues, and insufficient education of physicians. A new vaccine is feasible but will not be developed unless there is a demand by infectious diseases specialists, epidemiologists, authorities in affected states and the public that is evident to manufacturers. The fact that there is no vaccine for an infection causing ∼20,000 annual cases is an egregious failure of public health.

A disclosure dilemma: what you don't know can kill you, but so can what you do know.

No medical intervention comes without risks. Certain risks may be grave, but will only occur in a fractional percentage of cases. When does the disclosure of risks of this nature create more harm than good, leading patients to avoid therapies that, on balance, would provide significantly more benefit than risk? This article explores several high-profile disclosures of high severity/low probability risks in devices, drugs, and biologics that resulted in harmful unintended consequences. It contrasts the conflicting interests of manufacturers, the Food and Drug Administration (FDA), medical professionals and patients/consumers. It critiques several proposed approaches to the issue, then presents its own disclosure framework.

Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease.

Neuropathy following vaccination has been reported; however, biopsy-confirmed small fiber neuropathy has not been described. We report five patients who developed paresthesias within one day to two months following vaccination for rabies, varicella zoster, or Lyme disease. On examination, there was mild sensory loss in distal extremities, preserved strength, normal or minimally abnormal electrodiagnostic findings, and decreased epidermal nerve fiber densities per skin biopsy. Empiric immunomodulatory therapy was tried in two patients and was ineffective. All patients' symptoms have improved, but persist. We conclude that an acute or subacute, post-vaccination small fiber neuropathy may occur and follow a chronic course.

Human Lyme disease vaccines: past and future concerns.

The development of a vaccine for Lyme disease was intensely pursued in the 1990s. However, citing a lack of demand, the first human Lyme disease vaccine was withdrawn from the market less than 5 years after its approval. The public's concerns about the vaccine's safety also likely contributed to the withdrawal of the vaccine. Nearly a decade later, no vaccine for human Lyme disease exists. The expansion of Lyme disease's endemic range, as well as the difficulty of diagnosing infection and the disease's steady increase in incidence in the face of proven preventative measures, make the pursuit of a Lyme disease vaccine a worthwhile endeavor. Many believe that the negative public perception of the Lyme disease vaccine will have tarnished any future endeavors towards its development. Importantly, many of the drawbacks of the Lyme disease vaccine were apparent or foreseeable prior to its approval. These pitfalls must be confronted before the construction of a new, effective and safe human Lyme disease vaccine.

The Lyme vaccine: a cautionary tale.

People living in endemic areas acquire Lyme disease from the bite of an infected tick. This infection, when diagnosed and treated early in its course, usually responds well to antibiotic therapy. A minority of patients develops more serious disease, particularly after a delay in diagnosis or therapy, and sometimes chronic neurological, cardiac, or rheumatological manifestations. In 1998, the FDA approved a new recombinant Lyme vaccine, LYMErix, which reduced new infections in vaccinated adults by nearly 80%. Just 3 years later, the manufacturer voluntarily withdrew its product from the market amidst media coverage, fears of vaccine side-effects, and declining sales. This paper reviews these events in detail and focuses on the public communication of risks and benefits of the Lyme vaccine and important lessons learned.