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BACKGROUND: Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype-dependent manner. This study aimed to determine if HBGA status affected vaccine take of the G3P[6] neonatal vaccine RV3-BB. METHODS: DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take. RESULTS: In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 [95% CI, .94-1.06]; P = .97) or Lewis phenotype (relative risk, 1.03 [95% CI, .94-1.14]; P = .33), nor was a difference observed when analyzed by each component of vaccine take. CONCLUSIONS: The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.
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Antígenos de Grupos Sanguíneos , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Lactante , Recién Nacido , Humanos , Vacunas contra Rotavirus/genética , Indonesia , GenotipoRESUMEN
Maternal antibodies are passively transferred to the fetus via the placenta during gestation and can play an important role in protecting the newborn from infection. For example, in malaria-endemic regions, maternal antibodies likely provide substantial protection against Plasmodium falciparum malaria in the first 6 months of life. However, circulating maternal antibodies can also interfere with vaccine efficacy. Here, we used a mouse maternal transfer model to evaluate whether maternal antibodies interfere with the responsiveness to a virus-like particle (VLP)-based vaccine targeting the CIS43 epitope of the malaria circumsporozoite protein (CSP). We found immunized dams passively transfer to pups high levels of anti-CSP IgG antibodies that steadily decline as the animals age. We also found that the neonatal offspring of immunized mice do not respond to de novo immunization with the CIS43-targeted VLP vaccine until maternal antibody titers decline below an inhibitory threshold. These findings may have important implications for delineating the delicate balance between protection conferred by maternal antibodies and the offspring's ability to respond to immunization.
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Vacunas contra la Malaria , Malaria , Vacunas de Partículas Similares a Virus , Animales , Ratones , Embarazo , Femenino , Animales Recién Nacidos , Proteínas Protozoarias , Malaria/prevención & control , AnticuerposRESUMEN
Background: Neonatal death rates are high in sub-Saharan Africa and the majority of these deaths are preventable. Antenatal care (ANC) is a good channel for the reduction of neonatal deaths. This study aimed to assess newborn care practices among lactating women in Nigeria and determine their relationship with ANC attendance. Methodology: This was a cross-sectional survey involving 241 lactating mothers selected using the cluster sampling method. A structured interviewer-administered questionnaire was employed to obtain data. The Chi-square test was used to assess the associations between categorical variables. Logistic regression was used to determine the predictors of umbilical cord care, thermal care, and neonatal vaccination status. Good cord care was defined as having minimum of three appropriate practices concerning the use of clean instruments to tie the cord, use of clean instruments to cut the cord, and application of chlorhexidine, 70% alcohol, saltwater, or nothing on the cord), Results were presented as odds ratios (ORs). P < 0.05 was taken as statistically significant. Results: The mean age of participants was 29.0 ± 5.5 years. Most participants reported that sterile instruments were used to cut their baby's umbilical cords; that their babies were dried immediately after placenta delivery and that their babies were fully vaccinated (91.0%, 90.5%, and 85.1% respectively). ANC visits (aOR = 8.0, p = 0.02) and place of delivery (aOR = 10.6, p = 0.01) were significantly associated with good umbilical cord care practices. However, none of the participants' sociodemographic characteristics were significantly associated with newborn thermal care and vaccination status. Conclusion: The prevailing antenatal care services are ineffective in preparing mothers for newborn care. Place and frequency of ANC have positive associations with umbilical cord care. There is a need to implement quality ANC that will enhance maternal and neonatal outcomes and implement innovative interventions to enhance ANC attendance. The WHO positive pregnancy experience model should be implemented.
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Bacille-Calmette Guérin (BCG) modulates atherosclerosis development in experimental animals, but it remains unclear whether neonatal BCG vaccination is pro- or anti-atherogenic. Many animal models differ fundamentally from BCG administration to human infants in terms of age, vaccine preparation, dosing schedule, and route of administration. We aimed to elucidate the effect of neonatal subcutaneous BCG vaccinationanalogous to human BCG vaccinationon atherosclerosis development in ApoE−/− mice. At 2 days of age, a total of 40 ApoE−/− mice received either a weight-equivalent human dose of BCG, or saline, subcutaneously. From 4 weeks onwards, the mice were fed a Western-type diet containing 22% fat. At 16 weeks of age, mice were sacrificed for the assessment of atherosclerosis. Body weight, plasma lipids, atherosclerosis lesion size and collagen content were similar in both groups. Atherosclerosis lesion number was lower in mice that received BCG. Macrophage content was 20% lower in the BCG-vaccinated mice (p < 0.05), whereas plaque lipid content was increased by 25% (p < 0.01). In conclusion, neonatal BCG vaccination reduces atherosclerosis plaque number and macrophage content but increases lipid content in a murine model of atherosclerosis. Human epidemiological and mechanistic studies are warranted to investigate whether neonatal BCG vaccination is potentially atheroprotective.
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The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.
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Vacunas contra la Tuberculosis , Tuberculosis , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos/metabolismo , Animales , Antígeno de Maduración de Linfocitos B/metabolismo , Médula Ósea , Supervivencia Celular , Inmunidad Humoral , Interleucina-6/metabolismo , Ratones , Oligodesoxirribonucleótidos/metabolismo , Células Plasmáticas , Toxoide Tetánico , Tuberculosis/metabolismoRESUMEN
Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.
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Mycobacterium tuberculosis , Animales , Antígenos Bacterianos , Vacuna BCG , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Virus de la Coriomeningitis Linfocítica/genética , Ratones , Mycobacterium tuberculosis/genéticaRESUMEN
BACKGROUND: Rotavirus vaccine (RV) coverage levels for US infants are <80%. METHODS: We surveyed nationally representative networks of pediatricians by internet/mail from April to June, 2019. Multivariable regression assessed factors associated with difficulty administering the first RV dose (RV#1) by the maximum age. RESULTS: Response rate was 68% (303/448). Ninety-nine percent of providers reported strongly recommending RV. The most common barriers to RV delivery overall (definite/somewhat of a barrier) were: parental concerns about vaccine safety overall (27%), parents wanting to defer (25%), parents not thinking RV was necessary (12%), and parent concerns about RV safety (6%). The most commonly reported reasons for nonreceipt of RV#1 by 4 to 5 months (often/always) were parental vaccine refusal (9%), hospitals not giving RV at discharge from nursery (7%), infants past the maximum age when discharged from neonatal intensive care unit/nursery (6%), and infant not seen before maximum age for well care visit (3%) or seen but no vaccine given (4%). Among respondents 4% strongly agreed and 25% somewhat agreed that they sometimes have difficulty giving RV#1 before the maximum age. Higher percentage of State Child Health Insurance Program/Medicaid-insured children in the practice and reporting that recommendations for timing of RV doses are too complicated were associated with reporting difficulty delivering the RV#1 by the maximum age. CONCLUSIONS: US pediatricians identified multiple, actionable issues that may contribute to suboptimal RV immunization rates including lack of vaccination prior to leaving nurseries after prolonged stays, infants not being seen for well care visits by the maximum age, missed opportunities at visits and parents refusing/deferring.
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Infecciones por Rotavirus , Vacunas contra Rotavirus , Niño , Humanos , Inmunización , Lactante , Recién Nacido , Medicaid , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Estados Unidos , VacunaciónRESUMEN
Three recombinant Taenia ovis antigens (To45, To16, To18) each induce protective immunity in lambs or ewes against infection with T. ovis metacestodes. The degree and duration of immunity were assessed in lambs born from vaccinated ewes. Treatment group sizes varied, typically not fewer than 5 animals per group. Ewes were immunised with one T. ovis recombinant protein prior to lambing and the degree and duration of passive immunity in their lambs was assessed by challenge infection up to 18 weeks. Lambs were fully protected up to 6 weeks of age but immunity waned from 6 to 12 weeks and there was no protection when lambs were challenged at 15 weeks. Immunisation of lambs with the homologous recombinant antigen was not effective when vaccinations were given when maternal antibody was high. Lambs were effectively immunised in the presence of passively protective antibody when vaccinated with an antigen that was different to that given to ewes. Vaccination of lambs with a combination of two proteins, To16 and To18, was more effective than giving these single antigens and gave a significant reduction of cyst numbers when lambs were challenged 12 months after immunisation. These results indicate that the use of combinations of T. ovis recombinant antigens could enable complete protection of lambs against infection, if a delivery system becomes available that will maintain antibody at protective levels for 12 months. Alternatively, a third injection given at 6 months may promote the anamnestic response to give long lasting protection.
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Enfermedades de las Ovejas , Taenia , Teniasis , Vacunas , Animales , Antígenos , Femenino , Ovinos , Enfermedades de las Ovejas/prevención & control , Teniasis/prevención & control , Teniasis/veterinaria , Vacunación/veterinariaRESUMEN
BACKGROUND: Among elder children/young adults who received hepatitis B virus (HBV) vaccination during infancy, the serological status of HBsAg-negative and anti-HBc-positive [HBsAg(-)/anti-HBc(+)] was frequently reported, indicating potential occult HBV infection (OBI). It is required to define the long-term protection of neonatal vaccination against OBI in their mature adulthood. METHODS: Building upon the 1983-1990 established Qidong Hepatitis B Intervention Study, we sampled 10% of the 28-35-year-old participants, who remained in the cohort by 2012. Each participant was tested for serological markers of HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc. HBV-DNA and relaxed circular DNA (rcDNA) were determined in some HBsAg(-)/anti-HBc(+) individuals. RESULTS: Totally, 3615 individuals from the neonatal vaccination group and 3100 individuals from the control group donated blood samples, respectively. In the vaccination group, the prevalence of HBsAg was 1.58% (57/3615), HBsAg(-)/anti-HBc(+) was 4.70% (170/3615), significantly lower than in the control group, which was 7.45% (231/3100) and 19.48% (640/3100) respectively (all p < 0.001). With aging, HBsAg(-)/anti-HBc(+) prevalence increased in the sampled participants from the control group (pfor trend < 0.001), but uncertain from the vaccination group. Of HBsAg(-)/anti-HBc(+), HBV-DNA was detected in 13.08% (17/130) from the vaccination group, and in 4.18% (12/287) from the control group. HBV rcDNA was detected in most sera that were tested positive for HBV-DNA. CONCLUSIONS: OBI occurred in some vaccinated adults. However, neonatal HBV vaccination kept the effective protection against OBI in mature adults.
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Hepatitis B , Adulto , ADN Viral , Hemocromatosis , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Anticuerpos contra la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Vacunas contra Hepatitis B , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Humanos , Recién Nacido , VacunaciónRESUMEN
Childhood vaccines have been the cornerstone tool of public health over the past century. A major barrier to neonatal vaccination is the "immaturity" of the infant immune system and the inefficiency of conventional vaccine approaches at inducing immunity at birth. While much of the literature on fetal and neonatal immunity has focused on the early life propensity toward immune tolerance, recent studies indicate that the fetus is more immunologically capable than previously thought, and can, in some circumstances, mount adaptive B and T cell responses to perinatal pathogens in utero. Although significant hurdles remain before these findings can be translated into vaccines and other protective strategies, they should lend optimism to the prospect that neonatal and even fetal vaccination is achievable. Next steps toward this goal should include efforts to define the conditions for optimal stimulation of infant immune responses, including antigen timing, dose, and route of delivery, as well as antigen presentation pathways and co-stimulatory requirements. A better understanding of these factors will enable optimal deployment of vaccines against malaria and other pathogens to protect infants during their period of greatest vulnerability.
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Feto/inmunología , Inmunocompetencia , Vacunas contra la Malaria/administración & dosificación , Malaria/prevención & control , Inmunidad Adaptativa , Factores de Edad , Anticuerpos Antiprotozoarios/inmunología , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/parasitología , Femenino , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Esquemas de Inmunización , Recién Nacido , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/parasitología , Malaria/inmunología , Malaria/parasitología , Malaria/transmisión , Intercambio Materno-Fetal , Embarazo , VacunaciónRESUMEN
BACKGROUND/PURPOSE: This multicenter study aimed to evaluate the seroprevalence of hepatitis B virus (HBV) and the use of combination antiretroviral therapy (cART) among patients receiving HIV care in Taiwan. METHODS: We retrospectively reviewed the medical records of HIV-infected adult patients who initiated cART at 11 designated hospitals in Taiwan between 2012 and 2016. The clinical information collected included serological profiles on HBV, hepatitis C virus (HCV), and syphilis, plasma HIV RNA load, nadir CD4 cell count, and antiretrovirals with activity against both HBV and HIV (tenofovir disoproxil fumarate [TDF], lamivudine [LAM], and emtricitabine [FTC]). RESULTS: We analyzed 1800 HIV-infected patients; 1742 (96.8%) were male and 794 (44.1%) were born after July, 1986, when nationwide universal neonatal HBV vaccination was implemented. HBsAg positive results were 11.6% (209/1800), which decreased significantly from 18.1% (182/1006) in those born before July 1986 to 3.4% (27/794) in those born after. In multivariable analysis, HBsAg positivity was significantly associated with age (adjusted odds ratio [aOR] 1.06, 95% confidence interval [CI] 1.05-1.08), CD4â§200 cells/µL (aOR 0.73, 95% CI 0.53-0.99), and HCV seropositivity (aOR 1.62, 95% CI 1.06-2.50). Of 209 HBV/HIV-coinfected patients, 31.1% started cART containing only LAM with anti-HBV activity, while 68.9% started cART containing TDF plus LAM or coformulated TDF/FTC. CONCLUSIONS: The overall prevalence of HBV/HIV coinfection remained high among HIV-infected patients in Taiwan. Despite recommendations of the HIV treatment guidelines for the management of HBV infection, a substantial proportion of HIV/HBV-coinfected patients received cART containing only LAM for HBV infection.
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Infecciones por VIH/complicaciones , Hemocromatosis/epidemiología , Hemocromatosis/prevención & control , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Estudios Seroepidemiológicos , Adulto , Antirretrovirales/uso terapéutico , Biomarcadores , Recuento de Linfocito CD4 , Coinfección/tratamiento farmacológico , Femenino , Infecciones por VIH/tratamiento farmacológico , Hemocromatosis/inmunología , Hepatitis B/inmunología , Virus de la Hepatitis B , Humanos , Programas de Inmunización , Lamivudine/uso terapéutico , Masculino , Estudios Retrospectivos , Sífilis , Taiwán/epidemiología , Tenofovir , Adulto JovenRESUMEN
Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a pneumococcal conjugate vaccine, Pnc1-TT, could affect the expression of tumor necrosis factor receptor (TNF-R) superfamily members, known to be involved in the initiation and maintenance of antibody responses; B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA) and their ligands, BAFF, and a proliferation inducing ligand (APRIL). Initially we assessed the maturation status of different B cell populations and their expression of BAFF-R and BCMA. Neonatal mice had dramatically fewer B cells than adult mice and the composition of different subsets within the B cell pool differed greatly. Proportionally newly formed B cells were most abundant, but they had diminished BAFF-R expression which could explain low proportions of marginal zone and follicular B cells observed. Limited BCMA expression was also detected in neonatal pre-plasmablasts/plasmablasts. LT-K63 enhanced vaccine-induced BAFF-R expression in splenic marginal zone, follicular and newly formed B cells, leading to increased plasmablast/plasma cells, and their enhanced expression of BCMA in spleen and bone marrow. Additionally, the induction of BAFF and APRIL expression occurred early in neonatal mice immunized with Pnc1-TT either with or without LT-K63. However, BAFF+ and APRIL+ cells in spleens were maintained at a higher level in mice that received the adjuvant. Furthermore, the early increase of APRIL+ cells in bone marrow was more profound in mice immunized with vaccine and adjuvant. Finally, we assessed, for the first time in neonatal mice, accessory cells of the plasma cell niche in bone marrow and their secretion of APRIL. We found that LT-K63 enhanced the frequency and APRIL expression of eosinophils, macrophages, and megakaryocytes, which likely contributed to plasma cell survival, even though APRIL+ cells showed a fast decline. All this was associated with enhanced, sustained vaccine-specific antibody-secreting cells in bone marrow and persisting vaccine-specific serum antibodies. Our study sheds light on the mechanisms behind the adjuvanticity of LT-K63 and identifies molecular pathways that should be triggered by vaccine adjuvants to induce sustained humoral immunity in early life.
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Linfocitos B/inmunología , Toxinas Bacterianas/farmacología , Enterotoxinas/farmacología , Proteínas de Escherichia coli/farmacología , Inmunidad Humoral/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Animales , Animales Recién Nacidos , Linfocitos B/citología , RatonesRESUMEN
BACKGROUND: VP4 [P] genotype binding specificities of rotaviruses and differential expression of histo-blood group antigens (HBGAs) between populations may contribute to reduced efficacy against severe rotavirus disease. P[6]-based rotavirus vaccines could broaden protection in such settings, particularly in Africa, where the Lewis-negative phenotype and P[6] rotavirus strains are common. METHODS: The association between HBGA status and G3P[6] rotavirus vaccine (RV3-BB) take was investigated in a phase 2A study of RV3-BB vaccine involving 46 individuals in Dunedin, New Zealand, during 2012-2014. FUT2 and FUT3 genotypes were determined from DNA extracted from stool specimens, and frequencies of positive cumulative vaccine take, defined as an RV3-BB serum immune response (either immunoglobulin A or serum neutralizing antibody) and/or stool excretion of the vaccine strain, stratified by HBGA status were determined. RESULTS: RV3-BB produced positive cumulative vaccine take in 29 of 32 individuals (91%) who expressed a functional FUT2 enzyme (the secretor group), 13 of 13 (100%) who were FUT2 null (the nonsecretor group), and 1 of 1 with reduced FUT2 activity (i.e., a weak secretor); in 37 of 40 individuals (93%) who expressed a functional FUT3 enzyme (the Lewis-positive group) and 3 of 3 who were FUT3 null (the Lewis-negative group); and in 25 of 28 Lewis-positive secretors (89%), 12 of 12 Lewis-positive nonsecretors (100%), 2 of 2 Lewis-negative secretors, and 1 of 1 Lewis-negative weak secretor. CONCLUSIONS: RV3-BB produced positive cumulative vaccine take irrespective of HBGA status. RV3-BB has the potential to provide an improved level of protection in settings where P[6] rotavirus disease is endemic, irrespective of the HBGA profile of the population.
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Antígenos de Grupos Sanguíneos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Anticuerpos Antivirales/sangre , Estudios de Cohortes , Heces/enzimología , Fucosiltransferasas/genética , Humanos , Recién Nacido , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
FDA regulations require safety testing of constituent ingredients in drugs (21 CFR 610.15). With the exception of extraneous proteins, no component safety testing is required for vaccines or vaccine schedules. The dosing of aluminum in vaccines is based on the production of antibody titers, not safety science. Here we estimate a Pediatric Dose Limit that considers body weight. We identify several serious historical missteps in past analyses of provisional safe levels of aluminum in vaccines, and provide updates relevant to infant aluminum exposure in the pediatric schedule considering pediatric body weight. When aluminum doses are estimated from Federal Regulatory Code given body weight, exposure from the current vaccine schedule are found to exceed our estimate of a weight-corrected Pediatric Dose Limit. Our calculations show that the levels of aluminum suggested by the currently used limits place infants at risk of acute, repeated, and possibly chronic exposures of toxic levels of aluminum in modern vaccine schedules. Individual adult exposures are on par with Provisional Tolerable Weekly Intake "limits", but some individuals may be aluminum intolerant due to genetics or previous exposures. Vaccination in neonates and low birth-weight infants must be re-assessed; other implications for the use of aluminum-containing vaccines, and additional limitations in our understanding of neurotoxicity and safety levels of aluminum in biologics are discussed.
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Aluminio/efectos adversos , Inmunoterapia , Adulto , Aluminio/administración & dosificación , Animales , Peso Corporal , Niño , Preescolar , Humanos , Lactante , Inyecciones Intravenosas , RatonesRESUMEN
Newborns are considered difficult to protect against infections shortly after birth, due to their ineffective immune system that shows quantitative and qualitative differences compared to adults. However, here we show that a single vaccination of mice at birth with a replication-deficient live vaccine Modified Vaccinia Ankara [MVA] efficiently induces antigen-specific B- and T-cells that fully protect against a lethal Ectromelia virus challenge. Protection was induced within 2â¯weeks and using genetically modified mice we show that this protection was mainly T-cell dependent. Persisting immunological T-cell memory and neutralizing antibodies were obtained with the single vaccination. Thus, MVA administered as early as at birth induced immediate and long-term protection against an otherwise fatal disease and appears attractive as a new generation smallpox vaccine that is effective also in children. Moreover, it may have the potential to serve as platform for childhood vaccines as indicated by measles specific T- and B-cell responses induced in newborn mice vaccinated with recombinant MVA expressing measles antigens.
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Esquemas de Inmunización , Vacuna contra Viruela/administración & dosificación , Vacuna contra Viruela/inmunología , Virus Vaccinia/inmunología , Animales , Animales Recién Nacidos , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , Ectromelia Infecciosa/prevención & control , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunologíaRESUMEN
Chronic hepatitis B virus (HBV) infection within the Canadian Arctic is considered endemic (>2% prevalence). Within the Arctic region of Nunavut, a vaccination program targeted at newborn infants was initiated approximately 20years ago, along with interim grade school catch-up programs, with the result that individuals born after 1980 are presumed vaccinated. This study investigates the effectiveness of these programs and is the first seroepidemiological survey to determine HBV prevalence in Nunavut in the post-vaccination era. Anonymized serum specimens scheduled for destruction following medical testing were collected between April 2013 and April 2014 from individuals granting consent. Specimens were tested for HBV antibodies, surface antigen (HBsAg), and HBV DNA to perform molecular characterization. Four thousand eight hundred and two specimens (13% of the population) were collected, with a resulting median age of 29years (range 1week to 93years). The prevalence of antibody to the HBV core protein was 9.4%; however, a 10-fold decrease in the rate of HBV exposure was noted among those born after 1980 compared to those born before (1.8% vs. 19.8%, p<0.01). HBsAg positivity was primarily documented in individuals born before 1980 (2.5%), although cases still occurred among the vaccine age cohort (0.3%). HBV subgenotype B5 (previously B6) was the most prevalent genotype observed (81.8%) indicating persistence of locally acquired infection. Vaccine-based antibody as the sole serological marker was evident in the vaccine age cohort, although the rate of decay with increasing age was much greater than predicted (less than 10% in those aged 5-19years). Nearly two decades after the advent of HBV vaccination in Nunavut, HBV prevalence has decreased to 1.2%, indicating non-endemic prevalence. However, the persistence of infection and a lower than expected prevalence of vaccine-based immunity in the vaccine age cohort will require further investigation to understand the causes and consequences.
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Anticuerpos contra la Hepatitis B/sangre , Vacunas contra Hepatitis B/administración & dosificación , Hepatitis B Crónica/epidemiología , Hepatitis B/epidemiología , Programas de Inmunización , Adolescente , Factores de Edad , Niño , Preescolar , Estudios Transversales , ADN Viral/sangre , ADN Viral/genética , Femenino , Estudios de Seguimiento , Genotipo , Hepatitis B/inmunología , Hepatitis B/prevención & control , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas contra Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Lactante , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Nunavut/epidemiología , Prevalencia , VacunaciónRESUMEN
Tuberculosis remains a major public health hazard worldwide, with neonates and young infants potentially more susceptible to infection than adults. BCG, the only vaccine currently available, provides some protection against tuberculous meningitis in children but variable efficacy in adults, and is not safe to use in immune compromised individuals. A safe and effective vaccine that could be given early in life, and that could also potentiate subsequent booster immunization, would represent a significant advance. To test this proposition, we have generated gene-based vaccine vectors expressing Ag85B from Mycobacterium tuberculosis (Mtb) and designed experiments to test their immunogenicity and protective efficacy particularly when given in heterologous prime-boost combination, with the initial DNA vaccine component given soon after birth. Intradermal delivery of DNA vaccines elicited Th1-based immune responses against Ag85B in neonatal mice but did not protect them from subsequent aerosol challenge with virulent Mtb H37Rv. Recombinant adenovirus vectors encoding Ag85B, given via the intranasal route at six weeks of age, generated moderate immune responses and were poorly protective. However, neonatal DNA priming following by mucosal boosting with recombinant adenovirus generated strong immune responses, as evidenced by strong Ag85B-specific CD4+ and CD8+ T cell responses, both in the lung-associated lymph nodes and the spleen, by the quality of these responding cells (assessed by their capacity to secrete multiple antimicrobial factors), and by improved protection, as indicated by reduced bacterial burden in the lungs following pulmonary TB challenge. These results suggest that neonatal immunization with gene-based vaccines may create a favorable immunological environment that potentiates the pulmonary mucosal boosting effects of a subsequent heterologous vector vaccine encoding the same antigen. Our data indicate that immunization early in life with mycobacterial antigens in an appropriate vaccine setting can prime for protective immunity against Mtb.
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Aciltransferasas/inmunología , Adenoviridae/genética , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Portadores de Fármacos , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/prevención & control , Vacunas de ADN/inmunología , Aciltransferasas/genética , Administración a través de la Mucosa , Animales , Antígenos Bacterianos/genética , Carga Bacteriana , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos , Humanos , Pulmón/microbiología , Masculino , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/aislamiento & purificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento , Vacunas contra la Tuberculosis/administración & dosificación , Vacunas contra la Tuberculosis/genética , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
BACKGROUND: The aim of this study was to compare the cost effectiveness of the current Irish programme of universal BCG vaccination of infants versus a programme which considered selectively vaccinating high risk infants using decision analytical modelling. METHODS: The efficacy of the BCG vaccine was re-evaluated to inform a decision analytical model constructed to follow a birth cohort of vaccinated and unvaccinated infants over a 15 year time horizon. The number of life years gained (LYG) was the primary outcome measure and this was compared to the net cost of the vaccination strategies. RESULTS: In the base case analysis, the incremental cost effectiveness ratios (ICERs) for the universal strategy and selective strategy vs no vaccination were 204,373/LYG and 143,233/LYG respectively. When comparing the incremental difference in moving from the universal to the selective strategy, the selective strategy costs 1,055,692 less per 4.8 life years lost per birth cohort. One way sensitivity analyses highlighted that a move from the universal to the selective strategy was particularly sensitive to the estimate of vaccine efficacy against deaths, the cost of administering the vaccine and the multiplier used to apportion risk of contracting tuberculosis. Probabilistic analysis suggested that a move from a universal based strategy to a selective based strategy could be deemed cost effective (probability of cost effectiveness is 76.8 %). CONCLUSION: The results of the study support the protective effect of the BCG vaccine in infants and quantified the cost effectiveness of the current BCG vaccination strategy and the decremental difference in moving to a selective strategy. This analysis highlights that the additional protection offered by the universal vaccination strategy is small compared to that of the selective strategy. Consideration should therefore be given to the implementation of a selective vaccination strategy, and diverting resources to improve TB case management and control.
RESUMEN
Pneumococcus is a significant pathogen in neonates and in early infancy, particularly as a cause of invasive disease in sub-Saharan Africa where nasopharyngeal carriage rates are also exceptionally high. The pneumococcal-conjugate vaccines have now been rolled out in many high income settings and an increasing number of low and middle income countries. They have been highly effective at preventing vaccine serotype disease in infants. However, a window of susceptibility remains prior to the first vaccination at around six weeks of age. This paper summarizes the data available on both maternal and neonatal vaccination to prevent disease in newborns and early infancy and considers the key challenges and next steps for research in the field.
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Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/administración & dosificación , Complicaciones Infecciosas del Embarazo/prevención & control , Vacunación/estadística & datos numéricos , África del Sur del Sahara/epidemiología , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Infecciones Neumocócicas/epidemiología , Embarazo , Vacunas Conjugadas/administración & dosificaciónRESUMEN
BACKGROUND: Equine neonates have reduced humoral and cell-mediated immune responses compared to adult horses after administration of killed vaccines. As a basis for this study, we hypothesized that newborn foals can mount strong immune responses after vaccination with live Mycobacterium bovis BCG. METHODS: Healthy 4-day-old foals (n=7), 4-month-old foals (n=7) and adult horses (n=6) were vaccinated once with live M. bovis BCG. Age-matched animals (n=5 per group) were used as unvaccinated controls. Relative vaccine-specific immunoglobulin concentrations and whole blood mRNA expression of IFN-γ, IL-4, and IL-10 were measured prior to and 2, 4, 6, and 8 weeks after vaccination. Eight weeks after vaccination, delayed type hypersensitivity (DTH) responses were assessed by measuring the increase in double skin thickness after intradermal injection of purified protein derivative. RESULTS: Both groups of foals and adult horses responded with a significant increase in vaccine-specific total IgG, IgGa, IgGc, IgG(T), and IgM concentrations. In contrast, only adult horses mounted significant IgGb responses. Vaccine-specific concentrations of total IgG and IgGa were significantly higher in adult horses than in 4-day-old foals whereas IgGc responses were significantly higher in 4-day-old foals than in the other two age groups. Adult horses had significantly higher basal IFN-γ and IL-4 mRNA expression than both groups of foals but vaccination with M. bovis BCG did not significantly increase expression of these cytokines, regardless of age group. Immunized horses had significantly higher DTH responses than age-matched unvaccinated controls. DTH responses were significantly greater in both groups of vaccinated foals than in vaccinated adult horses. CONCLUSION: Despite a naïve immune system, newborn foals have the ability to mount robust antibody and cell-mediated immune responses to M. bovis BCG.