RA Treatments - T-Cell Inhibition
- THU0221: Abatacept Single Dose Does Not Prevent Immune Response to Tetanus and Pneumococcal Vaccine
- FRI0112: Abatacept Does Not Impair Host Resistence to Mycobacterium TB Infection in Mice
THU0221 A Single Dose of Abatacept Does Not Prevent the Development of a Positive Immune Response to Tetanus and Pneumococcal Vaccines
Corbol M, Tay LK, Leon F, Vratsanos. Bristol-Myers Squibb.
Abatacept (ABA) is a new FDA approved biologic for the treatment for rheumatoid arthritis (RA) that inhibits T cell co-stimulation. T cell activation may be necessary in order to generate an adequate humoral response to therapeutic vaccinations. Whether ABA treatment impairs such responses is unknown. The goal of these studies was to investigate the effect of a single infusion of ABA on antibody responses to tetanus toxoid (primarily a memory response to a T cell-dependent peptidic antigen) and 23-valent pneumococcal vaccine (a less T cell-dependent response to polysaccharide).
Methods: A single dose of ABA was administered in an open label study design to 79 healthy volunteers as follows:
- vaccinations on Day 1,no ABA administered;
- vaccinations on Day 1, ABA 750 mg on Day 14;
- ABA on Day 1, vaccinations on Day 14;
- ABA on Day 1, vaccinations on Day 56.
Subjects were excluded if they had received a tetanus booster or pneumococcal vaccine within 5 years, or had baseline (BL) anti-tetanus antibodies below clinically detectable levels. Anti-tetanus and anti-pneumococcal antibody titers were measured 14 and 28 days after vaccination. A positive response was defined as at least a 2-fold increase in antibody titer from BL.
Results: The proportions of subjects who achieved at least a 2-fold increase in antibody titers to tetanus are shown in the table below.
| Treatment | N | Responders 2 wks post-tetanus, n(%) | Responders 4 wks post-tetanus, n(%) |
| Vaccines/control | 20 | 18 (90) | 15 (75) |
| Vaccines/pre-ABA | 20 | 16 (80) | 13 (65) |
| Vaccines 2 wks post-ABA | 19 | 11 (58) | 12 (63) |
| Vaccines 8 wks post-ABA | 20 | 16 (80) | 14 (70) |
There was a decrease in number of responders to tetanus when the vaccine was administered 2 wks post-ABA treatment. With respect to pneumoccocus, the same trend was seen (data not shown). Overall, 70% of subjects responding to at least 3 serotypes, and 25-30% of subjects to >6 serotypes, of pneumococcus.
Conclusion: These data suggest that ABA does not significantly impair the ability of healthy subjects to respond to either tetanus or pneumococcal vaccination.
Editorial Comment: There are several cautionary notes here. First, this study was in healthy individuals not immunocompromised patients such as those with rheumatoid arthritis. Second, these data are presented by the manufacturer of abatacept. Given the reduction in vaccine responders when the vaccine is given two weeks after ABA infusion, it would seem most prudent at this time to vaccinate BEFORE infusing abatacept.
FRI0112 Abatacept Treatment Does Not Impair Host Resistance to Chronic Mycobacterium Tuberculosis (M. Tb) Infection in Mice
Haggerty HG, Bigbee, Gonchoroff DG, Flynn JL. Bristol-Myers Squibb and Univ of Pittsburgh
Tumor necrosis factor (TNF) inhibitors have been associated with an increased risk for tuberculosis in patients with rheumatoid arthritis (RA), primarily via dissemination from latent disease. Whether abatacept (ABA), the first FDA approved inhibitor of T cell co-stimulation, has similar potential is unknown as patients at risk for having latent TB were excluded from clinical trials with ABA.
Methods: C57BL/6 mice were infected with a low dose of M. Tb to induce chronic granulomatous infection in the lungs (by 4 mths post-infection). Mice were then randomized to either ABA (0.5 mg/mouse; Aba); anti-murine TNF antibody (positive control); or vehicle control, and treated for up to 16 wks.
Results: Mice treated with anti-TNF antibody exhibited 100% mortality by week 9 (mean survival time was 44 days). In addition, they lost 15-25% body weight, and had increased M. Tb loads in lung, lymph node and spleen. Anti-TNF treated mice had increased numbers of CD4+, CD8+ cells, and CD69+ cells in the lungs (115%, 101%, 194%) compared to vehicle controls (p < 0.05 for all 3 cell types).
In contrast, ABA and vehicle treated controls were indistinguishable. 100% of mice in both groups survived the 16 wks of treatment. There was no significant change in body weight, and no increase in bacterial load in internal organs in ABA- compared to vehicle-treated mice. In addition, the amount of gamma-interferon, and the numbers of CD4+, CD8+ and CD69+ cells, as well as other T cell subsets, in lungs and lymph nodes were not different between the two groups.
Conclusion: In a murine model of chronic TB infection, ABA did not impair host ability to contain the infection. In contrast, and consistent with previous reports, anti-TNF therapy in the same model led to bacterial dissemination and death.
Editorial Comment: The failure to include PPD positive individuals in clinical trials with abatacept has limited our ability to know whether this drug enhances susceptibility to M. Tb infections. Because CD4+ T cells and gamma-interferon play a critical role in the containment of M. Tb, this has been a concern. The data presented in this mouse model are highly encouraging in showing no increased risk for dissemination of TB in chronically infected mice. A cautionary note is that this result cannot be extrapolated to human beings, especially immunologically compromised hosts such as patients with RA. Nonetheless, it is encouraging to remember that the animal studies showing that anti-TNF therapy predisposes to dissemination of M. Tb were predictive of the human experience. As abatacept becomes more widely used in high risk areas for TB, we will hopefully be able to clarify the relevance of the mouse findings to humans.