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Pandemic Influenza Vaccine Responses in Solid Organ Transplant Recipients: Variable Responses


links image MACÉ M SCHUURMANS, MD FCCP
University Hospital Zurich
Zurich, Switzerland
mschuurmans@me.com


The recent report of vaccine responses in solid organ transplant (SOT) recipients by Siegrist CA et al1 examined the AS03-adjuvanted pandemic vaccine, which was widely used during the influenza pandemic (2009/2010). Because of their higher risk for complications, SOT recipients are a priority group for influenza vaccination. However vaccine responses from previous trials have frequently shown reduced immunologic responses. Therefore strategies to enhance immunogenicity are needed. One strategy is to add an adjuvant in order to increase the vaccine response. The main vaccine used in Europe during the pandemic was the oil-in-water squalene-based adjuvanted pandemic influenza vaccine (Pandemrix®; GlaxoSmithKline, Brentford, UK), which was licensed by the European medical Agency. Two doses of this AS03-adjuvanted split influenza A /09/H1N1 vaccine was recommended for all SOT recipients in Switzerland. The aim of this study was to identify determinants influencing vaccine responses and those groups that may fail to reach seroprotection, and thus identify those patients who may require additional preventive strategies. The Geneva researchers recruited subjects as a part of a multiple parallel cohort study to determine adverse reactions, changes in biomarkers of graft function and immune response after two doses of the vaccine in 216 SOT recipients and in 138 controls after one dose. Exclusion criteria were limited to failure to comply with the study protocol and to patients transplanted less than 3 months before vaccination.

Antibody responses were measured by haemaglutination inhibition and confirmed by microneutralization. Geometric mean titres (GMT) and seroprotection rates (GMT ≥ 40) were calculated. Safety monitoring was done with self-completed diaries during seven days after each immunization. The study was performed without funding from the pharmaceutical industry. The study population included 25 lung transplant recipients (LTRs), 27 heart transplant recipients (HTRs); the largest subgroup being the kidney transplant recipients (96 patients).

Adverse reactions were fewer in the transplant recipients than in controls and graft function remained unaffected. Seroprotection (defined as post-vaccination titre of ≥ 1:40) was achieved by only 70.3% of SOT recipients, with significant differences between groups (lung 34%, heart 72%, kidney 83 %, liver 83% and pancreas 85%) compared to 87% of controls (P<0.001). The weakest responses were elicited in LTRs. GMT remained threefold lower in SOT recipients than in controls (115 versus 340). Multivariate analysis identified increasing age, type of transplant and increasing blood levels of mycophenolate as being independently associated with weaker responses. In contrast, high blood levels of calcineurin inhibitors remained without significant influence on vaccine responses. Mycophenolate was being used by 92% of LTRs and 63% of HTRs, respectively. Immunization was generally well tolerated. Injection site pain was frequent, but significantly less frequent than in controls (86% versus 95%, respectively). None of the HTRs had evidence for rejection, 3 LTRs had more than 15% reduction of FEV1 explainable by reasons other than the vaccination and were fully reversible over time. For the whole cohort treated rejection episodes were rare (2/216; 0.9%).

The authors concluded that the squalene-based adjuvanted vaccine was safe in SOT recipients. However, even two doses of this influenza vaccine did not provide adequate protection for LTRs, particularly those with high mycophenolate blood levels. Additional prophylactic measures should therefore be considered for these high-risk groups.

This prospective study showed an acceptable safety profile for the AS03-adjuvanted pandemic vaccine, but insufficient seroprotection in a large proportion of heart and lung transplant recipients. Mycophenolate levels and age appear to negatively impact vaccine response. Insufficient vaccine responses in SOT recipients, as documented here, are assumed to be associated with reduced clinical effectiveness. This aspect, however, was not investigated in the present study and the results should not be interpreted to infer vaccination is not a worthwhile measure in these vulnerable transplant recipients. They should, however, raise questions for us about what else we can do to prevent potentially deadly influenza infection. Which additional prophylactic measure should be considered? It remains to be determined what additional measures may be feasible or effective. Until this is defined, it is wise to maintain a high level of clinical suspicion for influenza infection in heart and lung transplant recipients in order to diagnose and treat this infection early and reduce influenza-related morbidity and mortality.



Disclosure Statement: The author has no conflict of interest to disclose.

Reference:

  1. Siegrist CA, Ambrosioni J, Bel M, Combescure C, Hadaya K, Martin PY, Soccal PM, Berney T, Noble S, Meier S, Posfay-Barbe K, Grillet S, Kaiser L, van Delden C; H1N1 study group. Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine. Antivir Ther. 2012;17(5):893-903.