Waning long-term immunity after vaccination with the pneumococcal vaccine Prevnar-13
Early mortality and recurrent hospitalizations due to invasive pneumococcal disease (Streptococcus pneumoniae infection) are common for people with Sickle Cell Disease (SCD). Frequent pneumococcal vaccinations are administered to SCD patients in the US, reducing infections and increasing patient life expectancy. Unfortunately, recent research indicates that the currently licensed pneumococcal vaccines are not as effective in patients with SCD, which is associated with low antibody titers shortly after vaccination. Our group has shown that mice with SCD are not protected from infection after pneumococcal vaccination. Much like in SCD patients, we correlated this lack of protection with short-lived pneumococcal antibody titers after vaccination. An important finding from this work is that antibody titers do not recover after booster shots are given to SCD mice, indicating that there is a deficiency in the generation of both B-cell memory and long-lived plasma cells (which produce antibodies). Further compounding this problem, it has been shown that protective pneumococcal vaccine responses require specialized B-cells in the spleen and peritoneal cavity called B-1 B-cells, and we have previously shown that SCD mice have dramatically reduced numbers of B-1 cells in their spleens. We also observed reduced percentages of these cells in the blood of SCD patients when compared to healthy control subjects. Hence, we have found cellular and functional correlates in the SCD mouse model that may explain the reduced effectiveness of pneumococcal vaccines and increased susceptibility to infection in people with SCD. We are currently working on trying to understand the basic mechanism of impaired pneumococcal immunity in SCD mice with the aim of developing new vaccines and therapeutics to overcome this problem.
Exhaustion and impaired B-cell memory induction in response to Influenza virus vaccination
Severe disease due to infection with the pandemic H1N1 influenza virus became pronounced in people with SCD in 2009. Unfortunately, little work has been done to understand the immunological effectiveness of the influenza vaccine in adults with SCD so that such problems can be avoided in the future. After conducting a clinical study, we have found that many SCD subjects do not induce the production of hemagglutination inhibition (HI) titers after influenza vaccination, whereas Control subjects do. Flow cytometric analysis of the blood leukocytes has revealed that Control subjects induced B-cells to shift towards a memory phenotype, but this was again inconsistent among the SCD subjects. B-cells also appear to have higher expression of FcRL4 in SCD subjects, indicating that they may have an exhausted phenotype. Additional observations of baseline aberrations included elevated serum concentrations of the neutrophil chemokine GRO and the “pro-inflammatory antibody” IgG3. We are interested in pursuing the potential link between inhibition of B-cell memory induction and exhaustion in patients with SCD after influenza vaccination, with the goal of reformulating vaccines such that they increase long-term memory against this virus.
Vaccine safety and exaggerated inflammation
Recent studies have indicated that severe adverse reactions to vaccines containing the adjuvant aluminum hydroxide (Alum) may be occurring in SCD patients after inoculation. We have found that SCD mice experience high mortality almost immediately after vaccination with ovalbumin and Alum, which is associated increased levels of IL-1b, IL-6, and total protein in the bronchoalveolar lavage fluid (BALF) in these mice. These findings are akin to those observed in acute respiratory distress syndrome (ARDS). We are currently looking into mediators of inflammation as a possible cause of over-exuberant responses to Alum containing vaccines so that we can better understand how and why severe adverse reactions to vaccination are occurring in SCD patients.
Viral variants and sub-serotypes found in Foot and Mouth Disease Virus (FMDV) pose immense problems for vaccine developers, as existing vaccines provide inadequate cross protection. We have shown in mice that “xenoepitope substitution” of the immunodominant and highly mutable epitope found in the VP1 G-H loop results in immune refocusing to other (sub-dominant) epitopes. We are currently working with collaborators at Plum Island Animal Disease Center (PIADC) to test the current Ad5-FMD vaccine consturcted with xenoepitopes in the hypervarialbe region of the G-H loop in swine, with the aim to broaden immunity to multiple strains of the virus.