Outbreak of invasive pneumococcal disease among shipyard workers, Turku, Finland, May to November 2019.

We report an outbreak of invasive pneumococcal disease and pneumococcal pneumonia among shipyard workers, in Turku, Southwest Finland. In total, 31 confirmed and six probable cases were identified between 3 May and 28 November 2019. Streptococcus pneumoniae serotypes 12F, 4 and 8 were isolated from blood cultures of 25 cases. Occupational hygiene measures and vaccination of ca 4,000 workers are underway to control the outbreak at the shipyard.

Enhancement of Th2 responses to replicative herpes simplex virus type 1 vectors by immunomodulative chemotherapy.

Replicating, neuroattenuated gamma(1)34.5-deleted herpes simplex virus (HSV)-vectors are tools for experimental therapy of gliomas and autoimmune diseases. Immunomodulative treatment with Linomide (quinoline-3-carboxamide) has earlier been shown to facilitate some virus infections and reduce autoimmunity. Now we aimed at elucidating the safety of immunomodulatory therapy during infection of mice with HSV vectors. We focused on immunological and virological changes in the nervous system. BALB/c mice were infected intranasally with the HSV-1 recombinant viruses R3616, R3659 and R8306 (with mouse IL-4 transgene) and either treated with Linomide or left untreated as control groups. Treatment with Linomide was started 7 days before infection. Virological analysis consisted of viral culture and PCR for HSV DNA. Cytokine responses were studied with quantitative RT-PCR and EIA. Immunomodulatory treatment did not change the clinical course of infections. The expression of IL-4 and IL-10 in brains increased in Linomide-treated mice, particularly in infection with R8306. The expression of IL-23p19 was decreased in brains in Linomide-treated, vector-infected mice, in comparison with nontreated but virus-infected animals. Immunomodulatory treatment did not increase the viral load in brains in any of the mouse groups infected with R3616, R3659 or R8306. Immunomodulative treatment with Linomide did not compromise the safety of replicating HSV-vectors, not even the one with IL-4 transgene, suggesting that combination of immunomodulation with virotherapy may be beneficial in the treatment of certain diseases of the central nervous system. Further investigations are needed to elucidate the effects of immunomodulatory therapy in order to improve vector survival and efficacy of gene therapy.

Spread and replication of and immune response to gamma134.5-negative herpes simplex virus type 1 vectors in BALB/c mice.

We have previously shown that intracranial infection of herpes simplex virus type 1 (HSV-1) vector R8306 expressing interleukin-4 (IL-4) can abolish symptoms of experimental autoimmune encephalomyelitis, which is used as a model for human multiple sclerosis (Broberg et al., Gene Ther. 8:769-777, 2001). The aim of the current study was to search for means other than intracranial injection to deliver HSV-derived vectors to the central nervous system of mice. We also aimed to study the replication efficiency of these vectors in nervous system tissues and to elucidate the effects of the viruses on the immune response. We studied the spread and replication of the following viruses with deletions in neurovirulence gene gamma(1)34.5: R3616, R849 (lacZ transgene), R3659 (alpha-tk), R8306 (murine IL-4 transgene), and R8308 (murine IL-10 transgene). The samples were taken from trigeminal ganglia and brains of BALB/c mice after corneal, intralabial, and intranasal infection, and the viral load was examined by viral culture, HSV DNA PCR, and VP16 reverse transcription (RT)-PCR. The results show that (i) intranasal infection was the most efficient means of spread to the central nervous system (CNS) besides intracranial injection; (ii) the viruses did not grow in the culture from the brain samples, but the viral DNA persisted even until day 21 postinfection; (iii) viral replication, as observed by VP16 mRNA RT-PCR, occurred mainly on days 4 and 7 postinfection in trigeminal ganglia and to a low extent in brain; (iv) R3659, R8306, and R8308 showed reactivation from the trigeminal ganglia in explant cultures; (v) in the brain, the vectors spread to the midbrain more efficiently than to other brain areas; and (vi) the deletions in the R3659 genome significantly limited the ability of this virus to replicate in the nervous system. The immunological studies show that (i) the only recombinant to induce IL-4 mRNA expression in the brain was R8306, the gamma interferon response was very low in the brain for R3659 and R8306, and the IL-23p19 response to R8306 decreased by day 21 postinfection, unlike for the other viruses; (ii) Deltagamma(1)34.5 HSV vectors modulated the subsets of the splenocytes differently depending on the transgene; (iii) R3659 infection of the nervous system induces expression and production of cytokines from the stimulated splenocytes; and (iv) HSV vectors expressing IL-4 or IL-10 induce expression and production of both of the Th2-type cytokines from splenocytes. We conclude that the intranasal route of infection is a possible means of delivery of Deltagamma(1)34.5 HSV vectors to the CNS in addition to intracranial infection, although replication in the CNS remains minimal. The DNA of the HSV vectors is able to reside in the brain for at least 3 weeks. The features of the immune response to the vectors must be considered and may be exploited in gene therapy experiments with these vectors.