Human and Veterinary Vaccines for Lyme Disease.

Lyme disease (LD) is an emerging zoonotic infection that is increasing in incidence in North America, Europe, and Asia. With the development of safe and efficacious vaccines, LD can potentially be prevented. Vaccination offers a cost-effective and safe approach for decreasing the risk of infection. While LD vaccines have been widely used in veterinary medicine, they are not available as a preventive tool for humans. Central to the development of effective vaccines is an understanding of the enzootic cycle of LD, differential gene expression of Borrelia burgdorferi in response to environmental variables, and the genetic and antigenic diversity of the unique bacteria that cause this debilitating disease. Here we review these areas as they pertain to past and present efforts to develop human, veterinary, and reservoir targeting LD vaccines. In addition, we offer a brief overview of additional preventative measures that should employed in conjunction with vaccination.

[EFFECTIVENESS OF APPLICATION OF COMBINED THERAPY OF EARLY ERYTHEMA STAGE OF LYME DISEASE TAKING INTO CONSIDERATION IMMUNOGENESIS FEATURES].

AIM: Study innate and adaptive immunity in patients with migrating erythema, clinical effectiveness ofcombined therapy using Immunovac vaccine and dynamics of immunologic parame- ters as a result of the therapy. MATERIALS AND METHODS: 37 adult patients with migrating erythema were examined. The patients were divided into 2 groups: 1st gr. (14 individuals) - Immunovac by intranasal-subcutaneous method against the background of basic therapy; 2nd gr. (23 individuals) - 200 mg/day doxycycline therapy for 21 days. Phagocytic activity of blood neutrophils; TLRs expression on mononuclear leukocytes of peripheral blood (PBML) and skin cells in foci by flow cytometry with mAT against TLR2, 3, 4, 5, 6, 7, 8, 9 using flow cytometer FC-500; subpopulation composition of peripheral blood lymphocytes; levels of pro-, anti-inflammation and regulatory cytokines in blood sera by EIA method; IgG, 1gM, IgA in blood sera were studied in patients before treatment and 1 month after therapy. RESULTS: A high level of TLR2, 4, 7, 8 on skin cells in foci, TLR2, 4 - on blood cells; low content of CD95+ and CD25+, high-level of serum IL-lb, IL-2 and IL-4, an increase of general IgE level was detected in patients'with migrating erythema. Immunovac facilitated an increase of CD95+ and CD25+, IFN-y synthesis, reduced the level of general IgE in a more pronounced way than basic therapy. CONCLUSION: Inclusion of Immunovac into therapy of patients With migrating erythema facilitates increase of clinical effectiveness and correlates with correction of immunologic disorders.

Immunogenicity and safety of an 18-month booster dose of the VLA15 Lyme borreliosis vaccine candidate after primary immunisation in healthy adults in the USA: results of the booster phase of a randomised, controlled, phase 2 trial.

BACKGROUND: Incidence rates of Lyme borreliosis, a tickborne disease attributed to infection by Borrelia species, are increasing, and limitations to existing treatments potentiate the possibility of severe outcomes. Nevertheless, there are no licensed vaccines for Lyme borreliosis prevention in humans. This study investigated the immunogenicity and safety of a booster dose of VLA15, an investigational outer surface protein A (OspA)-based Lyme borreliosis vaccine that has previously shown safety and immunogenicity when administered as a primary vaccination series, following a primary VLA15 vaccination series. METHODS: We report the results of the booster phase of a randomised, observer-blinded, placebo-controlled, multicentre, phase 2 study that enrolled healthy adults aged 18-65 years from five US clinical study centres to receive 135 µg or 180 µg VLA15 or placebo at months 0, 2, and 6 in the main study phase. Participants who received 180 µg VLA15 in the main study phase and did not have relevant protocol deviations were eligible for the booster phase (months 18-30). Participants were randomly reassigned (2:1) to receive an intramuscular injection of a VLA15 booster or placebo 1 year after the completion of primary vaccination (month 18) via a randomisation list generated by an unmasked statistician with a block size of six. Individuals involved in data safety monitoring, rerandomisation, vaccine handling, and vaccine accountability were unmasked; the study sponsor and statisticians were only unmasked after analysis of data up to 1 month after booster administration. All other individuals remained masked throughout the booster phase. The outcomes for the booster phase were the immunogenicity (evaluated in the booster per-protocol population) and safety (evaluated for all participants who received the booster) of the booster dose up to month 30. The study is registered at ClinicalTrials.gov (NCT03970733) and is completed. FINDINGS: Between Feb 4 and March 23, 2021, 58 participants (28 men and 30 women) were screened, randomly assigned, and received VLA15 (n=39) or placebo (n=19). One participant in the placebo group was lost to follow-up. The IgG geometric mean titres for each OspA serotype (serotypes 1-6) in the VLA15 group peaked at 1 month after the booster dose (1277·0 U/mL [95% CI 861·8-1892·3] to 2194·5 U/mL [1566·8-3073·7] vs 23·6 U/mL [18·1-30·8] to 36·8 U/mL [26·4-51·3] in the placebo group [p<0·0001 for all serotypes]), remained elevated at month 24 (137·4 U/mL [95·8-196·9] to 265·8 U/mL [202·9-348·2] vs 22·3 U/mL [17·7-28·0] to 29·1 U/mL [20·8-40·6] in the placebo group; p<0·0001 for all serotypes), and declined by month 30 (54·1 U/mL [38·6-75·7] to 101·6 U/mL [77·6-133·1] vs 21·9 U/mL [18·0-26·6] to 24·9 U/mL [19·0-32·6] in the placebo group; p<0·0001 for all serotypes except serotype 1 [p=0·0006]). Solicited local adverse events were reported more frequently in the VLA15 group (35 [92%, 95% CI 79-97] of 38 participants) than the placebo group (six [32%, 15-54] of 19 participants; p<0·0001) after booster vaccination. There was no significant difference in the frequency of solicited systemic adverse events between groups (20 [59%, 42-74] of 34 participants in the VLA15 group vs six [38%, 18-61] of 16 participants in the placebo group). Related unsolicited adverse events (none severe) were reported by two (5%, 1-17) of 39 participants in the VLA15 group and none (0%, 0-17) of 19 participants in the placebo group. There were no severe solicited local or systemic adverse events or deaths during the study. INTERPRETATION: A booster dose of VLA15 is safe and induces substantial anamnestic immune responses against all six OspA serotypes. As with previously investigated OspA-based Lyme borreliosis vaccines, waning immune responses were observed with VLA15, and annual boosters might therefore be required. FUNDING: Valneva.

Optimisation of dose level and vaccination schedule for the VLA15 Lyme borreliosis vaccine candidate among healthy adults: two randomised, observer-blind, placebo-controlled, multicentre, phase 2 studies.

BACKGROUND: Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1-6, which are associated with the most common pathogenic Borrelia species in Europe and North America. METHODS: Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18-65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 µg (study one only), 135 µg, or 180 µg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 µg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed. FINDINGS: For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 µg VLA15, 215 to 135 µg, 205 to 180 µg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 µg VLA15, 100 to 180 µg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4-119·0) to 267·4 units per mL (serotype 3; 194·8-367·1) for 90 µg VLA15, 101·9 (serotype 1; 87·1-119·4) to 283·2 units per mL (serotype 3; 248·2-323·1) for 135 µg, and 115·8 (serotype 1; 98·8-135·7) to 308·6 units per mL (serotype 3; 266·8-356·8) for 180 µg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9-361·0) to 545·2 units per mL (serotype 2; 431·8-688·4) for 135 µg VLA15 and 274·7 (serotype 1; 209·4-360·4) to 596·8 units per mL (serotype 3; 471·9-754·8) for 180 µg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91-96 vs 26%, 19-34; study two: 96%, 93-98 vs 35%, 24-49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65-73 vs 43%, 34-52; study two: 74%, 67-80 vs 51%, 38-64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48-57) of participants in the VLA15 groups and 52% (43-60) of those in the placebo groups; for study two these were 65% (58-71) and 69% (55-80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1-4; study two: 4%, 2-7) and adverse events of special interest (study one: 1%, 0-2; study two: 1%, 0-3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported. INTERPRETATION: VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 µg dose and 0-2-6-month schedule, which was associated with the greatest immune responses. FUNDING: Valneva.

Novel recombinant vaccinia virus-vectored vaccine affords complete protection against homologous Borrelia burgdorferi infection in mice.

The rising prevalence of Lyme disease (LD) in North America and Europe has emerged as a pressing public health concern. Despite the availability of veterinary LD vaccines, no vaccine is currently available for human use. Outer surface protein C (OspC) found on the outer membrane of the causative agent, Borrelia burgdorferi, has been identified as a promising target for LD vaccine development due to its sustained expression during mammalian infection. However, the efficacy and immunological mechanisms of LD vaccines solely targeting OspC are not well characterized. In this study, we developed an attenuated Vaccinia virus (VV) vectored vaccine encoding type A OspC (VV-OspC-A). Two doses of the VV-OspC-A vaccine conferred complete protection against homologous B. burgdorferi challenge in mice. Furthermore, the candidate vaccine also prevented the development of carditis and lymph node hyperplasia associated with LD. When investigating the humoral immune response to vaccination, VV-OspC-A was found to induce a robust antibody response predominated by the IgG2a subtype, indicating a Th1-bias. Using a novel quantitative flow cytometry assay, we also determined that elicited antibodies were capable of inducing antibody-dependent cellular phagocytosis in vitro. Finally, we demonstrated that VV-OspC-A vaccination generated a strong antigen-specific CD4+ T-cell response characterized by the secretion of numerous cytokines upon stimulation of splenocytes with OspC peptides. This study suggests a promising avenue for LD vaccine development utilizing viral vectors targeting OspC and provides insights into the immunological mechanisms that confer protection against B. burgdorferi infection.

Immunogenicity of the Lyme disease antigen OspA, particleized by cobalt porphyrin-phospholipid liposomes.

Outer surface protein A (OspA) is a Borrelia lipoprotein and an established Lyme disease vaccine target. Admixing non-lipidated, recombinant B. burgdorferi OspA with liposomes containing cobalt porphyrin-phospholipid (CoPoP) resulted in rapid, particulate surface display of the conformationally intact antigen. Particleization was serum-stable and led to enhanced antigen uptake in murine macrophages in vitro. Mouse immunization using CoPoP liposomes that also contained a synthetic monophosphoryl lipid A (PHAD) elicited a Th1-biased OspA antibody response with higher IgG production compared to other vaccine adjuvants. Antibodies were reactive with intact B. burgdorferi spirochetes and Borrelia lysates, and induced complement-mediated borreliacidal activity in vitro. One year after initial immunization, mice maintained high levels of circulating borreliacidal antibodies capable of blocking B. burgdorferi transmission from infected ticks to human blood in a feeding chamber.

Enhanced protective efficacy of Borrelia burgdorferi BB0172 derived-peptide based vaccine to control Lyme disease.

Lyme disease (LD) accounts for over 70% of tick-borne disease reported in the United States. The disease in humans is characterized by skin rash, arthritis, cardiac and neurological signs. Vaccination is the most efficient preventive measure that could be taken to reduce the incidence of the LD worldwide; however, at present no vaccine is available. In this study, evaluation of the Borrelia burgdorferi BB0172-derived peptide (PepB) in conjugated formulations was investigated as a vaccine candidate in murine model of LD. In brief, PepB was conjugated to the Cross-Reacting Material 197 (CRM197) and to Tetanus Toxoid heavy chain (TTHc) molecules, and subsequently used to immunize C3H/HeN mice. Following the challenge with 105 spirochetes/mouse via subcutaneous inoculation, TTHc:PepB construct showed protection in 66% of the immunized animals. Hence, to further evaluate the efficacy of TTHc:PepB, immunized mice were challenged with B. burgdorferi using the tick model of infection. The outcome of this experiment revealed that serum from TTHc:PepB immunized mice was borrelicidal. After tick infection, bacterial burden was significantly reduced (over 70%) in vaccinated animals when compared with the control groups regardless of whether the mice were infested 8 or 12-weeks post-priming. Therefore, we conclude that PepB conjugated antigens can serve as an alternative to prevent LD; nevertheless, further studies will be needed to dissect the mechanisms by which anti-PepB IgG antibodies are able to kill B. burgdorferi in vitro and in vivo to further advance in the development of formulations and delivery alternative to generate a safe anti-LD vaccine.

A study with a commercial vaccine against Lyme borreliosis in horses using two different vaccination schedules: Characterization of the humoral immune response.

A total of 143 horses were included in a study to test a commercial vaccine against Lyme borreliosis. The vaccine contained three different antigens (outer surface protein A, OspA) to prevent the infection with spirochetes - B.burgdorferi sensu stricto, B. afzelii and B. garinii. Horses in Group A (49 animals) received two vaccinations on days 0 and 14 and a booster on day 365, whereas 50 horses in Group B received an additional booster vaccination on day 180. Group C (44 animals) was not immunized. Total antibody levels and specific OspA antibody responses were assessed quantitatively and qualitatively in two-month intervals over 13-month period. Vaccinees in Groups A and B developed high OspA antibodies levels, whereas horses in Group C did not show specific antibody responses. The additional vaccination applied in Group B enhanced the specific OspA antibody response significantly and prevented its rapid decline.

Recombinant E. coli Dualistic Role as an Antigen-adjuvant Delivery Vehicle for Oral Immunization.

Escherichia coli is the mainstay tool for fundamental microbiology research due to its ease of cultivation and safety. Auxotrophic strains of the K-12 and B lineages of E. coli are the organisms of choice to produce recombinant proteins. Components present in the cell envelope of bacteria are also potent immune modulators and have been used to develop adjuvants. We used live E. coli, after induction of recombinant protein expression, to develop a vehicle which has a dualistic function of producing vaccine while presenting itself as the adjuvant to deliver oral vaccines against a number of infectious diseases, including Lyme disease. Here, we give an example using E. coli expressing B. burgdorferi Outer Surface Protein A, which was proven effective in reducing B. burgdorferi burden in infected ticks after a 5-year field trial of a baited formulation containing this reservoir targeted vaccine.

Vaccination of horses with Lyme vaccines for dogs induces short-lasting antibody responses.

Borrelia burgdorferi can induce Lyme disease. Approved Lyme vaccines for horses are currently not available. In an effort to protect horses, veterinarians are using Lyme vaccines licensed for dogs. However, data to assess the response of horses to, or determine the efficacy of this off-label vaccine use are missing. Here, antibodies against outer surface protein A (OspA), OspC, and OspF were quantified in diagnostic serum submissions from horses with a history of vaccination with canine Lyme vaccines. The results suggested that many horses respond with low and often short-lasting antibody responses. Subsequently, four experimental vaccination trials were performed. First, we investigated antibody responses to three canine vaccines in B. burgdorferi-naïve horses. One killed bacterin vaccine induced antibodies against OspC. OspA antibodies were low for all three vaccines and lasted less than 16weeks. The second trial tested the impact of the vaccine dose using the OspA/OspC inducing bacterin vaccine in horses. A 2mL dose produced higher OspA and OspC antibody values than a 1mL dose. However, the antibody response again quickly declined, independent of dose. Third, the horses were vaccinated with 2 doses of a recombinant OspA vaccine. Previous vaccination and/or environmental exposure enhanced the magnitude and longevity of the OspA antibody response to about 20weeks. Last, the influence of intramuscular versus subcutaneous vaccine administration was investigated for the recombinant OspA vaccine. OspA antibody responses were not influenced by injection route. The current work highlights that commercial Lyme vaccines for dogs induce only transient antibody responses in horses which can also be of low magnitude. Protection from infection with B. burgdorferi should not be automatically assumed after vaccinating horses with Lyme vaccines for dogs.

An evaluation of a Lyme disease prevention program in a working population.

PURPOSE: Lyme disease vaccine was offered to New York State Department of Health employees considered at risk for Lyme disease because of their job duties. This evaluation was conducted to assess (1) attitudes that affected employees' decisions to accept or decline the vaccine, (2) preventive behaviors among employees who received the vaccine, and (3) effectiveness of the educational modalities offered in improving knowledge of Lyme disease and Lyme disease vaccine. METHODS: A total of 190 eligible employees were identified and were offered two educational modalities before deciding whether to receive the vaccine. The subsequent evaluation involved three telephone interviews, one pre-education and two posteducation-vaccination, to assess factors affecting the decision about vaccination and attitudes, behaviors, and knowledge among vaccine recipients (N=30) and nonrecipients (N=160). RESULTS: This evaluation indicated that the majority of vaccine recipients decided to receive the vaccine because of an anticipated risk of tick exposure. For employees who declined vaccination, many were concerned about the safety (64%), novelty (56%), or efficacy (48%) of the vaccine. Posteducation knowledge of Lyme disease vaccine significantly improved among those who attended an education session compared with those who did not and was retained 1 year later. DISCUSSION: The results suggest that when a vaccine-related disease-prevention program is undertaken, (1) attitudes about disease risks and vaccine risks influence decisions to accept vaccination, and (2) in-person education should be a mandatory element of the program.

Lyme borreliosis in 2005, 30 years after initial observations in Lyme Connecticut.

Nearly 100 years ago, Afzelius described a patient with an expanding skin lesion, called erythema migrans, which is now known to be the initial skin manifestation of Lyme borreliosis. Approximately 70 years later, in 1976, epidemiologic evaluation of a cluster of children with arthritis in Lyme, Connecticut led to a complete description of the infection. During the subsequent years, investigators in a number of countries have made remarkable strides in the elucidation of this tick-borne spirochetal infection. The purpose of this review is to discuss the current status of Lyme borreliosis, including areas in which knowledge of the infection is still incomplete.

What we have learned about Lyme borreliosis from studies in children.

Although pediatric Lyme borreliosis (LB) need not be a separate nosological entity, there are clinically important differences in presentation, antibiotic regimens and outcomes in children, which provide lessons that can be extrapolated to the disease as it affects adults. A large proportion of the worldwide data is obtained from children. The aim of this presentation is not to present an exhaustive review of the pediatric literature, but to review a selection of pediatric studies that have made a significant contribution to our body of knowledge in Lyme borreliosis.

Live Attenuated Borrelia burgdorferi Targeted Mutants in an Infectious Strain Background Protect Mice from Challenge Infection.

Borrelia burgdorferi, B. garinii, and B. afzelii are all agents of Lyme disease in different geographic locations. If left untreated, Lyme disease can cause significant and long-term morbidity, which may continue after appropriate antibiotic therapy has been administered and live bacteria are no longer detectable. The increasing incidence and geographic spread of Lyme disease are renewing interest in the vaccination of at-risk populations. We took the approach of vaccinating mice with two targeted mutant strains of B. burgdorferi that, unlike the parental strain, are avirulent in mice. Mice vaccinated with both strains were protected against a challenge with the parental strain and a heterologous B. burgdorferi strain by either needle inoculation or tick bite. In ticks, the homologous strain was eliminated but the heterologous strain was not, suggesting that the vaccines generated a response to antigens that are produced by the bacteria both early in mammalian infection and in the tick. Partial protection against B. garinii infection was also conferred. Protection was antibody mediated, and reactivity to a variety of proteins was observed. These experiments suggest that live attenuated B. burgdorferi strains may be informative regarding the identification of protective antigens produced by the bacteria and recognized by the mouse immune system in vivo Further work may illuminate new candidates that are effective and safe for the development of Lyme disease vaccines.

Prevention of Lyme borreliosis.

Lyme borreliosis, the most common tick-borne disease in both North America and Europe, is acquired through the bite of certain tick species in the genus Ixodes. The number of Ixodes ticks in the environment can be reduced by relatively simple interventions such as removing leaf litter and brush, which increases exposure of the tick to sun and air and takes advantage of the tick's vulnerability to desiccation, or by application of acaricides to property. Deer elimination or exclusion, application of topical acaricides to mice or deer, and application of systemic acaricides to deer are more complex approaches. However, none of these methods for reducing tick numbers, nor any of the recommended personal prevention measures, such as reducing the amount of exposed skin, use of tick repellents on exposed skin or clothing, and frequent tick checks to remove attached ticks expeditiously, has been demonstrated to decrease significantly the incidence of Lyme borreliosis in humans. Only two strategies have been shown to do so. A recombinant outer surface protein A (OspA) vaccine was approximately 80% effective in clinical trials in the United States, and a single 200 mg dose of doxycycline given within 72 hours of an I. scapularis tick bite, was shown to be 87% effective. The OspA vaccine is no longer manufactured due to poor sales. Consequently, single-dose doxycycline prophylaxis is rapidly gaining acceptance in the United States. Limiting single-dose doxycycline to just the highest risk tick bites can be accomplished if the health care provider has learned to differentiate engorged from unengorged I. scapularis ticks. Limitations of single-dose doxycycline prophylaxis are that the majority of patients with Lyme borreliosis do not recall a tick bite, and that there is no evidence that other Ixodes transmitted infections, such as human granulocytic ehrlichiosis, would be prevented. A safe, effective, inexpensive and well-accepted vaccine would be welcome.

Asymptomatic infection with Borrelia burgdorferi.

The natural history of asymptomatic seroconversion to Borrelia burgdorferi has been unclear. We report here, on the basis of a post hoc assessment, the frequency and outcome of asymptomatic seroconversion to B. burgdorferi in participants of a large Lyme disease vaccine trial. We show that infection with B. burgdorferi may be asymptomatic but that asymptomatic infection is unusual in the United States.

Lyme vaccine: issues and controversies.

The development of an effective vaccine for Lyme disease represents a major advance in the control of the most prevalent vector-borne disease in the United States. It has a definite place in the total approach to control of this disease. Its use should be restricted to individuals who are at moderate to high risk of exposure to infected vector ticks. Vaccinated individuals should not be complacent about other personal protection measures, because the vaccine is not uniformly effective and protective antibody levels decay rapidly. Booster doses will be necessary, but the intervals have not yet been determined. There is a theoretical concern about the possible induction of inflammatory arthritis through an autoimmune mechanism, but there is no evidence that this condition has clinical relevance. The impact of the current lawsuits on vaccine recommendations and use remains to be determined. Continued surveillance for rare long-term side effects should address the medical risk issue. Alternative primary vaccine administration schedules are currently under study, and could lead to regimens permitting achievement of protective immunity in 6 months or less. Vaccine is not approved for use in children under the age of 15 years.

Safety and immunogenicity profile of a recombinant outer-surface protein A Lyme disease vaccine: clinical trial of a 3-dose schedule at 0, 1, and 2 months.

OBJECTIVES: This study compared the tolerability of a Lyme disease vaccine administered intramuscularly at 0 and 1 months with that of a vaccine administered at 0, 1, and 2 months to determine (1) whether adding a third dose of vaccine 1 month after the second would affect the safety profile, and (2) whether a shortened vaccination schedule of 0, 1, and 2 months would provide an immune response similar to that obtained with vaccine administered at 0, 1, and 12 months. BACKGROUND: An efficacy trial of a Lyme disease vaccine had demonstrated safety and efficacy against definite (clinically manifested and laboratory-confirmed) Lyme disease after 3 doses at 0, 1, and 12 months and resulted in 90% of subjects having titers > or =1400 enzyme-linked immunosorbent assay units (EL.U)/mL (the proposed seroprotective level for 1 tick season). METHODS: This multicenter, open-label, prospective, randomized study assessed the safety and efficacy of different doses of a recombinant outer-surface protein A (OspA) vaccine in 956 volunteers aged 17 to 72 years from 3 Lyme disease-endemic sites. Blood samples were collected at months 0, 2, 3, 12, and 13 to assess total immunoglobulin-G anti-OspA titers. RESULTS: Most adverse events were transient and mild to moderate. The geometric mean antibody titer increased 2.8-fold from month 2 (1786 EL.U/mL to 4842 EL.U/mL), and approximately 90% of the volunteers had a titer > or =1400 and 99% had a titer > or =400 EL.U/mL (the mini- mum seroprotective level at any given time) after the third dose. An antibody kinetics model predicts that protection would last for a typical tick-transmission season. CONCLUSIONS: In volunteers aged 17 to 72 years, 3 doses of vaccine administered in 2 months was well tolerated, more immunogenic than 2 doses, and provided a higher probability of protection before exposure or travel to Lyme disease-endemic areas.