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Publisher's version (útgefin grein), Aim: The aim was to estimate the impact of the 10-valent pneumococcal vaccine (PHiD-CV) on tympanostomy tube placements (TTP) in children under five years of age in Iceland. Methods: This population-based observational cohort study followed 11 consecutive birth-cohorts 2005–2015 from birth until their fifth birthday. Population registries were merged using national identification numbers. The risk of TTP was compared between birth-cohorts adjusted for the number of previous otitis media diagnoses and antimicrobial prescriptions. A Cox regression model was applied and the hazard ratio (HR) of TTP was estimated between each birth-cohort and the last vaccine non-eligible birth-cohort. The vaccine impact of PHiD-CV10 on TTP was estimated as 1-HR ×100%. Results: In total, 51 247 children were followed for 210 724 person-years, of which 14 351 underwent 20 373 procedures. The estimated vaccine impact on TTP was −6% (95% CI −16% to 2.7%). Children in the vaccine-eligible cohorts had fewer previous otitis media diagnoses and had been prescribed fewer antimicrobials prior to the procedure than children in the vaccine non-eligible cohorts. Conclusion: Despite high uptake of PHiD-CV10, tympanostomy procedures increased in Iceland during the study period. Vaccine-eligible children had milder disease prior to the procedure. The reason underlying these findings are speculative., An investigator-initiated study funded by GlaxoSmithKline Biologicals SA. Additionally, a grant was received from the Landspitali University Hospital Research Fund. GlaxoSmithKline Biologicals SA was provided the opportunity to review a draft version of this manuscript, but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript.

Streptococcus pneumoniae is a Gram-positive diplococcus that is both a commensal bacterium in the upper respiratory tract of humans, and a common pathogen. The infectious manifestations of pneumococci span a range from benign to serious; from acute otitis media (AOM) that often resolves without intervention, to sepsis and meningitis which invariably require hospitalization. Despite its often benign course, AOM is the most common reason for physician visits and antimicrobial prescriptions in children. Likewise, tympanostomy tube placements are the most common surgical procedure requiring general anesthesia in children. Pneumococcal vaccinations have a long history, beginning in 1914 with clinical trials in humans. A 23-valent polysaccharide vaccine was marketed in 1983, but was poorly immunogenic in children. The seven-valent pneumococcal conjugate vaccine became available in 2000. Multiple studies have demonstrated that it offered protection against AOM, tympanostomy tube placements, pneumonia and invasive disease in children. Indirect protection in adults has also been demonstrated. Higher valency vaccines were later developed. In April of 2011, the 10-valent pneumococcal Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV10) was introduced in Iceland. The aim of the study was to evaluate the impact of PHiD-CV10 introduction in Iceland. Special attention was paid to the healthcare burden of children: visits to primary care and to the emergency department of Children‘s Hospital Iceland for AOM, antimicrobial prescriptions, tympanostomy tube placements, and hospitalizations for pneumonia and invasive disease. The population-based impact of PHiD-CV10 was examined, including whether herd effect occurred in adults. Finally, the study focused on estimating the cost-effectiveness of PHiD-CV10 in Iceland. Individual level data were obtained from five population-based registries and Landspitali University Hospital‘s patient registry for the period from 1 January 2005 to 31 December 2017. Data on all administered doses of pneumococcal vaccines and all outpatient antimicrobial prescriptions were extracted from the National Vaccine and National Drug Prescription Registries of the Icelandic Directorate of Health. Visits for respiratory infections were extracted from the Primary Care Registry and Landspitali University Hospital‘s patient registry, and data on tympanostomy procedures were obtained from Icelandic Health Insurance‘s reimbursement database. Immigration and emigration data were provided by Statistics Iceland. Four cohort studies followed 11 Icelandic birth-cohorts 2005-2015. The first such study followed children from birth to 36 months of age with regards to primary care visits for AOM. An Andersen-Gill model that corrected for age, gender and the number of previous AOM visits was applied. The vaccine impact was calculated as (1 - hazard ratio between the last vaccine eligible and last vaccine non-eligible cohort) * 100%, and revealed a 22% reduction in AOM with a 95% confidence interval (CI) 12% to 31%. The incidence of ceftriaxone-treated AOM at Children‘s Hospital Iceland was examined before and after vaccine introduction to estimate the impact on AOM with treatment failure, and revealed a 55% (95% CI 46%-63%) reduction in ceftriaxone-treatment episodes. The second cohort study followed children from birth to 36 months of age with regards to outpatient antimicrobial prescriptions. The same methods were used to calculate vaccine impact. A 5.8% (95% CI 1.6%-9.8%) decrease in the number of prescriptions was established. The third cohort study evaluated tympanostomy procedures. It followed children from birth to 60 months of age and revealed a non-significant increase in procedures, despite the introduction of PHiD-CV10. The fourth cohort study examined the hazard of hospitalization for respiratory and invasive infections. It compared vaccine eligible cohorts to vaccine non-eligible cohorts and found a 20% (95% CI 5%-33%) reduction in pneumonia hospitalizations. A population-based study that included all age-groups, estimated the cost-effectiveness of PHiD-CV10 and examined whether herd effect had occurred. A Bayesian time series methodology was used and included visits and hospitalization for diagnoses unrelated to the vaccine as controls. The study revealed strong evidence of herd effect for otitis media, pneumonia and invasive disease. When taking into account costs avoided because of prevented disease, the introduction of PHiD-CV10 was found to have saved 7,463,176 United States Dollars in the first five years of the program. The studies that comprise this thesis showed a large societal impact of PHiD-CV10 introduction; visits, antimicrobial prescriptions and hospitalizations of children decreased, and indirect protection was observed in adults. The vaccination program was cost-saving from both the health sector and societal perspectives., Streptococcus pneumoniae er Gram-jákvæð baktería sem getur valdið sýkingum í mönnum. Pneumókokkar eru hluti af eðlilegri örveruflóru nefkoks flestra barna, en einnig algengur sjúkdómsvaldur bæði staðbundina og ífarandi sýkinga. Alvarleiki þeirra spannar breitt bil: frá miðeyrnabólgum, sem ganga flestar yfir án inngrips, til blóðsýkinga og heilahimnubólga sem krefjast innlagnar á sjúkrahús. Þrátt fyrir að miðeyrnabólgur séu mildar sýkingar, þá eru þær algengasta orsök læknisheimsókna og sýklalyfjaávísana barna. Rörísetningar í eyru eru algengustu aðgerðir hjá börnum sem krefjast svæfingar. Bólusetningar gegn pneumókokkum eiga sér langa sögu. Fyrstu tilraunir í mönnum áttu sér stað 1914. Fjölsykrubóluefni var fyrst þróað árið 1945 en náði ekki útbreiðslu fyrr en 1983, þegar 23-gilt fjölsykrubóluefni kom á markaðinn. Það vakti hins vegar ófullnægjandi ónæmissvar hjá börnum. Til þess þurfti próteintengingu. Sjö-gilt próteintengt pneumókokka bóluefni kom á markaðinn árið 2000. Fjöldi rannsókna hefur sýnt fram á að notkun þess verndi gegn miðeyrnabólgum, rörísetningum, lungnabólgum og ífarandi sýkingum hjá börnum. Einnig hefur verið sýnt fram á hjarðónæmi hjá fullorðnum. Samtengd bóluefni gegn 10 og 13 hjúpgerðum pneumókokka voru framleidd í kjölfarið. Í apríl 2011 var 10-gilda samtengda pneumókokka bóluefnið innleitt í ungbarnabólusetningar á Íslandi. Markmið þessarar rannsóknar var að meta lýðgrunduð áhrif innleiðingar 10-gilda samtengda pneumókokka bóluefnisins á Íslandi. Sérstök áhersla var lögð á að meta notkun barna á heilbrigðisþjónstu: komur þeirra á heilsugæslu og bráðamóttöku Barnaspítala Hringsins vegna miðeyrnabólgu; sýklalyfjaávísanir og rörísetningar. Einnig voru skoðaðar innlagnir barna á sjúkrahús vegna miðeyrnabólgu, lungnabólgu, blóðsýkingar og heilahimnubólgu. Lýðgrunduð áhrif bólusetningarinnar voru einnig skoðuð og metið hvort hjarðónæmi hafði myndast hjá fullorðnum. Að lokum var markmið rannsóknarinnar að meta kostnaðarvirkni bóluefnisins á Íslandi. Einstaklingsgögnum var safnað úr fimm lýðgrunduðum gagnagrunnum og sjúkraskrám Landspítala Háskólasjúkrahúss fyrir tímabilið 1. Janúar 2005- 31. Desember 2017. Öllum pneumókokkabólusetningum og sýklalyfjaávísunum var safnað úr bólusetningargagnagrunni og lyfjagagnagrunni Embættis Landlæknis. Allar læknisheimsóknir vegna öndunarfærasýkinga voru dregnar úr samskiptaskrá heilsugæslustöðva og sjúkraskrá Landspítala Háskólasjúkrahúss, og upplýsingar um rörísetningar fengust úr endurgreiðslugrunni Sjúkratrygginga Íslands. Upplýsingar um búferlaflutninga barna til og frá Íslandi voru sóttar til Hagstofu Íslands. Fjórar ferilsrannsóknir voru framkvæmdar sem fylgdu eftir fæðingarárgöngum 2005-2015. Sú fyrsta fylgdi öllum börnum frá fæðingu til 36 mánaða aldurs með tilliti til koma á heilsugæslu vegna miðeyrnabólgu. Andersen-Gill líkan var notað sem leiðrétti fyrir aldri, kyni og fjölda fyrri koma vegna miðeyrnabólgu. Áhrif bólusetningarinnar voru metin sem (1 - áhættuhlutfallið milli síðasta bólusetta og síðasta óbólusetta árgangsins) * 100%, sem reyndist vera 22% með 95% öryggisbil 12%-31%. Tíðni ceftriaxone meðferðar við miðeyrnabólgu á Barnaspítala Hringsins var notuð til að áætla áhrif á bóluefnisins á alvarlegar miðeyrnabólgur, og reyndist vera 55% minni í kjölfar bólusetningarinnar með 95% öryggisbili 46%-63%. Önnur ferilrannsóknin fylgdi börnum eftir til 36 mánaða aldurs með tilliti til allra sýklalyfjaávísanna. Sama líkan var notað og áhrifin metin á sama hátt. Sýklalyfjaávísunum fækkaði um 5.8% með 95% öryggisbil 1.6%-9.8%. Þriðja ferilrannsóknin mat tíðni rörísetninga. Hún fylgdi börnum eftir til 60 mánaða aldurs og sýndi fram á ómarktæka aukningu á rörísetningum, þrátt fyrir innleiðingu bóluefnisins. Fjórða rannsóknin skoðaði sjúkrahúsinnlagnir vegna öndunarfærasýkinga. Hún bar saman bólusetta árganga við óbólusetta og sýndi fram á 20% fækkun á innlögnum vegna lungnabólgu, 95% öryggisbil 5%-33%. Lýðgrunduð rannsókn sem tók til allra aldurshópa mat hjarðónæmi og kostnaðarvirkni bóluefnisins. Rannsókninin beitti aðferðum Bayes á tímaraðgreiningu og notaði komur og innlagnir vegna annarra sjúkdóma til samanburðar. Rannsóknin sýndi fram á sterkt hjarðónæmi sem leiddi til fækkunar á miðeyrnabólgum, lungnabólgum og ífarandi sýkingum. Að teknu tilliti til sparnaðar vegna færri sýkinga, sparaði bóluefnið 7,463,176 Bandaríkjadala á fyrstu fimm árum eftir innleiðingu þess. Rannsóknirnar sem þessi ritgerð er byggð á sýndu fram á gríðarlegan samfélagslegan ábáta af innleiðingu pneumókokkabóluefnisins á Íslandi. Innleiðingin olli fækkun á læknisheimsóknum, sjúkrahúsinnlögnum og sýklalyfjaávísunum hjá börnum og hjarðónæmi myndaðist hjá fullorðnum. Að teknu tilliti til sparnaðar vegna færri sýkinga sparaði innleiðing bóluefnisins íslenskt samfélag 7,463,176 Bandaríkjadala á föstu 2015 verðlagi.

Publisher's version (útgefin grein), Vaccination with pneumococcal conjugate vaccines (PCVs) disrupts the pneumococcal population. Our aim was to determine the impact of the 10-valent PCV on the serotypes, genetic lineages, and antimicrobial susceptibility of pneumococci isolated from children in Iceland. Pneumococci were collected between 2009 and 2017 from the nasopharynges of healthy children attending 15 day care centers and from the middle ears (MEs) of children with acute otitis media from the greater Reykjavik capital area. Isolates were serotyped and tested for antimicrobial susceptibility. Whole-genome sequencing (WGS) was performed on alternate isolates from 2009 to 2014, and serotypes and multilocus sequence types (STs) were extracted from the WGS data. Two study periods were defined: 2009 to 2011 (PreVac) and 2012 to 2017 (PostVac). The overall nasopharyngeal carriage rate was similar between the two periods (67.3% PreVac and 61.5% PostVac, P = 0.090). Vaccine-type (VT) pneumococci decreased and nonvaccine-type (NVT) pneumococci (serotypes 6C, 15A, 15B/C, 21, 22F, 23A, 23B, 35F, and 35B) significantly increased in different age strata post-PCV introduction. The total number of pneumococci recovered from ME samples significantly decreased as did the proportion that were VTs, although NVT pneumococci (6C, 15B/C, 23A, and 23B) increased significantly. Most serotype 6C pneumococci were multidrug resistant (MDR). Serotype 19F was the predominant serotype associated with MEs, and it significantly decreased post-PCV introduction: these isolates were predominantly MDR and of the Taiwan19F-14 PMEN lineage. Overall, the nasopharyngeal carriage rate remained constant and the number of ME-associated pneumococci decreased significantly post-PCV introduction; however, there was a concomitant and statistically significant shift from VTs to NVTs in both collections of pneumococci., This was an investigator-initiated study funded by GlaxoSmithKline Biologicals SA. Grants were received from the Landspitali University Hospital Research Fund, the Eimskip University Fund, the Wellcome Trust (research fellowship 083511/Z/07/Z and grant 04992/Z/14/Z to A.B.B.), and the John Fell Fund (grant 123/734 to A.B.B.). Work at the Wellcome Sanger Institute was supported by the Wellcome core funding (grant 206194 to S.D.B.)

Publisher's version (útgefin grein). Publisher’s Note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Background: Antimicrobial resistance is a public-health threat and antimicrobial consumption is the main contributor. The ten-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic vaccination program in 2011. The aim was to estimate the vaccine impact of PHiD-CV10 on outpatient antimicrobial prescriptions in children. Methods: Eleven Icelandic birth-cohorts (2005–2015) were followed from birth until three years of age or to the end of the study period (December 31, 2016). Birth-cohorts were grouped as vaccine non-eligible (VNEC, 2005–2010) or vaccine eligible (VEC, 2011–2015). Data on primary care visits for respiratory infections and antimicrobial prescriptions were extracted from two national registers. Using national identification numbers, prescriptions were linked to physician visits if filled within three days of the visit. Incidence rates and incidence rate ratios between VNEC and VEC were calculated. An Andersen-Gill model was used to model the individual level data, accounting for repeated events and censoring. Vaccine impact was calculated as (1 – Hazard Ratio) × 100%. Results: Included were 53,510 children who contributed 151,992 person-years of follow-up and filled 231,660 antimicrobial prescriptions. The incidence rate was significantly lower in the VEC compared to the VNEC, 144.5 and 157.2 prescriptions per 100 person-years respectively (IRR 0.92, 95%CI 0.91–0.93). Children in VEC were more likely to have filled zero (IRR 1.16 (95%CI 1.10–1.23) and 1–4 (IRR 1.08 95%CI 1.06–1.11) prescriptions compared to children in VNEC. The vaccine impact of PHiD-CV10 against all-cause antimicrobial prescriptions was 5.8% (95%CI 1.6–9.8%).When only considering acute otitis media-associated prescriptions, the vaccine impact was 21.8% (95%CI 11.5–30.9%). Conclusion: The introduction of PHiD-CV10 lead to reduced antimicrobial use in children, mainly by reducing acute otitis media episodes. This intervention therefore reduces both disease burden and could slow the spread of antimicrobial resistance., An investigator-initiated study funded by GlaxoSmithKline Biologicals SA. Additionally, a grant was received from the Landspitali University Hospital Research Fund. GlaxoSmithKline Biologicals SA was provided the opportunity to review a draft version of this manuscript, but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript.

The geographic remoteness of the Faroe Islands makes the archipelago an ideal location for research on bacterial carriage, their clonality, and vaccine studies. However, previous studies are lacking and the limited availability of necessary data has limited such investigations. The novel data collection and analysis presented in this thesis provides valuable knowledge on the antibacterial resistances in the three human bacterial pathogens - Group A Streptococcus (GAS), Escherichia coli and pneumococci in the Faroes. Data on antibacterial sales were compiled from the National Pharmacist in the Faroe Islands, Icelandic Medicines Agency, NOMESCO and DANMAP. Clinical oropharynx and urine samples were collected from patients by general practitioners in the years 2009, 2010 and in 2012. Nasopharyngeal swabs were collected from healthy children attending day-care centres from January to March in 2009, 2010 and 2011. Invasive pneumococcal isolates from the Faroe Islands were obtained from Statens Serum Institut in Denmark. All samples were identified and pneumococcal isolates were serotyped in two laboratories, one in the Faroe Islands and one in Iceland. Susceptibility testing was done according to CLSI and EUCAST standards using conventional methods. During the period 1999 to 2011, antibacterial sales were highest in Iceland, followed by the Faroe Islands and Denmark – with 21.8, 17.7 and 16.3 daily defined dose (DDD)/1000 inhabitants/day (DID), respectively. The most noteworthy difference was the higher sales of tetracycline in Iceland. The sales of the sub-groups, penicillins and macrolides differed significantly between the three countries. Erythromycin was mainly prescribed to children aged 0-4 years in the Faroe Island. Among GAS isolates from Faroese patients, the resistance of tetracycline decreased markedly between 2009 and 2010 (37% to 10%) and erythromycin resistance dropped in Iceland from 2008 (44%) to 2009 (5%). In the Faroe Islands, non-susceptibility was found in 54% of E. coli isolates with non-susceptibility to ampicillin being the most common (46%), followed by sulfamethoxazole (39%), trimethoprim (27%), and trimethoprim/sulfamethoxazole (27%). A significant correlation was found between antibacterial sales and antibacterial resistance. Our novel logistic modelling approach identified two categories of antibacterial agents – those that result in a marked increase in E. coli resistance and those with a moderate impact. Of the 607 children screened for pneumococci, 50% were carriers in 2009, 40% in 2010 and 42% in 2011. Antibiotic resistance in pneumococci was rare both in carriers and invasive disease patients. Five penicillin non-susceptible pneumococci (PNSPs) were found in carriers (1.8%) and one was found among the invasive isolates (1.7%). The most common serotypes in carriage (6B and 6A in 2009, 3 and 6C in 2010 and 11 and 6C in 2011) and among invasive pneumococcal diseases (IPD), 7F and 3. In conclusion, the association between antibacterial resistance and antibacterial use justifies a re-evaluation of antibacterial policies regarding treatment of UTIs. The pneumococcal carriage prevalence in children attending day-care centres is low and antibacterial resistance in pneumococci is presently rare. The prevalence of PNSPs was low compared to Iceland and Denmark. The established vaccine program in 2008 appears to have reduced incidence of PCV-7/13 serotype among IPD, and there is, furthermore, an indication of a subsequent serotype shift in pneumococcal carriage. Our logistic model facilitates representative predictions of the future developments in resistance with increased antibiotic sales and provides a valuable tool which can be used by resistance monitoring programs in other communities. Furthermore, by comparing results related to the Faroese population with the neighboring countries, Iceland and Denmark, we provide the first assessment of our community’s status with regards to the global multi-resistance threat., Landfræðileg einangrun Færeyja gerir eyjaklasann að ákjósanlegum stað fyrir rannsóknir á beratíðni baktería, klónasamsetningu þeirra og bólusetningarannsóknir. Engu að síður eru slíkar rannsóknir ekki fyrir hendi og takmarkaður aðgangur að nauðsynlegum gögnum hefur takmarkað slíkar rannsóknir. Þau nýju gögn og greiningar sem birtast í þessari ritgerð gefa mikilvægar upplýsingar um sýklalyfjaónæmi hjá þremur meinvaldandi bakteríum í mönnum – streptókokkum af flokki A (GAS), Escherichia coli og pneumókokkum í Færeyjum. Upplýsingar um sölu sýklalyfja fengust frá Lyfjafræðingi Færeyja, Lyfjastofnun Íslands, NOMESCO og DANMAP. Hálsstrokum og þvagsýnum var safnað af heilsugæslulæknum frá sjúklingum á árunum 2009, 2010 og 2012. Nefkoksstrokum var safnað frá heilbrigðum börnum á leikskólum í janúar til mars á árunum 2009, 2010 og 2011. Pneumókokkar úr ífarandi sýkingum í Færeyjum fengust frá Statens Seruminstitut, Danmörku. Öll sýni voru greind og pneumókokkastofnar hjúpgreindir í tveimur rannsóknastofum, einni í Færeyjum og einni á Íslandi. Næmispróf voru gerð í samræmi við CLSI og EUCAST aðferðir og staðla. Á árunum 1999 til 2011 var sala sýklalyfja mest á Íslandi, síðan Færeyjum en minnst í Danmörku með 21,8, 17,7 og 16,3 staðlaða dagskammta (DDD) á 1000 íbúa á dag (DID). Það sem bar mest á milli var mikil notkun tetrasýklín lyfja á Íslandi. Einnig var marktækur munur á sölu undirflokka penisillína og makrólíða milli þessara landa. Eryþrómýsín var einkum ávísað á 0-4 ára börn í Færeyjum. Tetrasýklín ónæmi hjá GAS frá Færeyskum sjúklingum minnkaði mikið frá 2009 til 2010 (37% til 10%) og eryþrómýsín ónæmi minnkaði á Íslandi frá 2008 (44%) til 2009 (5%). Í Færeyjum fannst minnkað næmi hjá 54% E. coli stofna, þar sem ampisillín ónæmi var algengast (46%), síðan súlfamethoxazol (39%), trímetóprím (27%) og trímetóprím/súlfamethoxazol (27%). Það var marktæk fylgni á milli sölu sýklalyfja og sýklalyfjaónæmis. Ný nálgun okkar með notkun tölfræðilíkans greindi sýklalyf í tvo flokka, þau sem leiddu til mikillar aukningar á ónæmi hjá E. coli og þau sem höfðu aðeins miðlungs áhrif. Af þeim 607 börnum sem tekin voru sýni frá til greiningar á pneumókokkum, þá reyndust 50% bera bakteríuna árið 2009, 40% 2010 og 42% 2011.Sýklalyfjaónæmi var sjaldgæft hjá pneumókokkum, bæði í berum og sjúklingum með ífarandi sjúkdóm. Fimm stofnar frá berum reyndust vera með minnkað næmi fyrir penisllíni (PNSP, 1,8%) og einn frá ífarandi sýkingum (1,7%). Algengustu hjúpgerðirnar í berum voru 6B og 6A árið 2009, 3 og 6C árið 2010 og 11 og 6C árið 2011, og í ífarandi sýkingum 7F og 3. Álykta má að tengslin á milli sýklalyfjaónæmis og sýklalyfjanotkunar réttlæti endurmat á stefnu við val á sýklalyfjum við þvagfærasýkingum. Beratíðni pneumókokka í börnum á leikskólum er lág og sýklalyfjaónæmi sjaldgæft. Algengi pneumókokka með minnkað næmi fyrir penisillíni var lágt í samanburði við Ísland og Danmörku. Bólusetningaráætlunin frá 2008 virðist hafa fækkað PCV-7/13 hjúpgerðum í ífarandi sýkingum og auk þess eru vísbendingar um hjúpgerðarbreytingar hjá pneumókokkum í berum. Tölfræðilíkanið auðveldar okkur að gera raunhæfar spár um þróun ónæmis samfara aukinni sölu sýklalyfja og gæti gagnast öðrum þjóðum í eftirliti þeirra með sýklalyfjaónæmi. Með því að bera saman niðurstöður tengdar færeysku þjóðinni við niðurstöður nágrannalandanna Íslands og Danmörku, fæst i fyrsta sinn mat á stöðu Færeyja í samhengi við þá alheimsógn sem stafar af fjölónæmum bakteríum.

Neonatal foals respond poorly to conventional vaccines. These vaccines typically target T-helper (Th) cell dependent B-cell activation. However, Th2-cell immunity is impaired in foals during the first three months of life. In contrast, neonatal basophils are potent interleukin-4 (IL-4) producers. The purpose of this study was to develop a novel vaccine triggering the natural capacity of neonatal basophils to secrete IL-4 and to evaluate if vaccination resulted in B-cell activation and antibody production against EHV-1 glycoprotein C (gC). Neonatal vaccination was performed by oral biotinylated IgE (IgE-bio) treatment at birth followed by intramuscular injection of a single dose of streptavidin-conjugated gC/IL-4 fusion protein (Sav-gC/IL-4) for crosslinking of receptor-bound IgE-bio (group 1). Neonates in group 2 received the intramuscular Sav-gC/IL-4 vaccine only. Group 3 remained non-vaccinated at birth. After vaccination, gC antibody production was not detectable. The ability of the vaccine to induce protection was evaluated by an EHV-1 challenge infection after weaning at 7 months of age. Groups 1 and 2 responded to EHV-1 infection with an earlier onset and overall significantly increased anti-gC serum antibody responses compared to control group 3. In addition, group 1 weanlings had a decreased initial fever peak after infection indicating partial protection from EHV-1 infection. This suggested that the neonatal vaccination induced a memory B-cell response at birth that was recalled at weanling age after EHV-1 challenge. In conclusion, early stimulation of neonatal immunity via the innate arm of the immune system can induce partial protection and increased antibody responses against EHV-1., Funding for this project was provided by the Harry M. Zweig Memorial Fund for Equine Research at Cornell University ‘A Novel Strategy to Boost Antibody Production to EHV-1 in Neonates’ (http://vet.cornell.edu/research/Zweig/). Monoclonal antibody development for horse cell surface markers and cytokines was supported by USDA grant #2005-01812 ‘The US Veterinary Immune Reagent Network’ and #2015-67015-23072 ‘Equine Immune Reagents: Development of monoclonal antibodies to improve the analysis of immunity in horses’ (https://nifa.usda.gov/).