To Örebro University

The mRNA vaccines have proven to be very effective in preventing severe disease and death from SARS-CoV-2 in the general population. However, in patients with chronic kidney disease (CKD) in dialysis or with kidney transplants (KT) the vaccine responses vary, with severe breakthrough infections as a consequence. In this intervention study we investigated the magnitude and quality of the responses to mRNA vaccination administered prior to kidney replacement therapy (KRT). Twenty patients with CKD G4/5 and nine healthy controls were followed for 12 months after receiving two doses of BNT162b2 four weeks apart and a booster dose after 3-6 months. Induction of anti-Spike and anti-RBD IgG in plasma followed the same kinetics in CKD patients and controls, with a trend towards higher titers in controls. In accordance, there was no differences in the establishment of Spike-specific memory B-cells between groups. In contrast, the CKD patients showed lower levels of anti-Spike IgG in saliva and Spike-specific CD8+ + T-cells in blood, possibly influencing the capacity of viral clearance which can contribute to an elevated risk of severe breakthrough infections. In conclusion, we found that CKD patients, despite having a reduced mucosal and cytotoxic immunity to BNT162b2, demonstrated a serological response in plasma similar to healthy controls. This suggests that immunization prior to RRT is efficient and motivated. (EudraCT-nr 2021-000988-68).

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

This paper discusses challenges in formulating and harmonizing malaria prevention recommendations for travellers. It explores diverse approaches used by advisory groups to assess malaria risk and shares insights from the 2023 International Expert Committee for Travel Medicine meeting. It also explores future prospects for enhancing malaria prevention recommendations for travellers.

Qdenga® has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4-16-year old's living in endemic areas. For individuals 16-60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

Vaccines have saved millions of lives, but for some individuals with a defective immune system the protection may be uncertain. This thesis aims to assess the immune response following viral vaccines in immunocompromised patients and in other groups at-risk.

In paper I the immune response to a modified vaccine schedule against hepatitis A, adding an extra vaccine dose, was tested in patients with rheumatoid arthritis (RA) on immunomodulating drugs. Following two doses,88% of RA patients developed seroprotective antibodies against hepatitis A compared to 94% of healthy controls. In paper II 53 cases of Tick borne encephalitis (TBE) vaccine failure were characterized. The majority of cases were seen in men, 81% were 50 years or older and 51% had co-morbidities. Vaccine failure was most common after three or four doses only, but was seen in up to nine doses. Four out of five had a moderate to severe disease. In paper III the immune response to mRNA vaccines was compared in SARS-CoV-2 experienced and naïve health care workers. Experienced individuals had an increased innate immune cell activation, cytokine and chemokine production and changes in innate gene expression following the first vaccine dose as well as a stronger adaptive response with higher antibody titres and B-cell and CD4+ T-cell activity. The differences were less after the second dose, but three doses were required before an equal immune response was observed in naïve and experienced individuals. In paper IV the immune response to SARS-CoV-2 mRNA vaccine was assessed in patients with chronic kidney disease (CKD) stage 4 and 5 prior to renal replacement therapy. CKD patients were found to have an immune response comparable with healthy controls, with the exception of lower secreted anti-spike antibodies in the saliva and a decreased cytotoxic CD8+ T-cell activity.

In conclusion, a deeper understanding of the immune response to vaccines is needed to be able to adapt recommendations and improve outcome in vulnerable groups

BACKGROUND: Southern Sweden is endemic for tick borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. The aim of this study was to describe cases of vaccine failures, and to optimize future vaccination recommendations.

METHODS: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in the county of Stockholm during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least two doses. Clinical data were extracted from medical records.

RESULTS: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group the median age was 62 years (6-83). Forty-three (81%) patients were over 50 years of age and two were children. Approximately half of the patients had comorbidities with diseases affecting the immune system accounting for 26% of all cases.Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases.

CONCLUSION: To our knowledge, this is the largest documented cohort of TBE-vaccine failures. Vaccine failure after five TBE-vaccine doses is rare. Our data provides rationale for adding an extra priming dose to the age group 50 years and older.

Background: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion.

Method: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months.

Results: Two months after the initial vaccination, 84% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies.

Conclusion: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients.