HLA genotypes and rubella vaccine immune response: Additional evidence

Recent population-based studies have demonstrated the genetic heritability of rubella vaccine response and assessed that the HLA system may explain about 20% of the inter-individual variance in humoral immune response to this vaccine. Our earlier studies compared HLA allelic associations with rubella vaccine-specific antibodies between two smaller cohorts of healthy Rochester, MN, children (346 and 396 subjects) after two doses of rubella-containing vaccine. This study found that specific HLA alleles were consistently associated with rubella-specific antibody titers (B*27:05, DPA1*02:01, and DPB1*04:01 alleles). The current study examined HLA associations in an independent larger cohort of 1012 healthy San Diego, CA, subjects (age 19–40 years) after rubella vaccine in order to replicate our previous findings in the Rochester subjects. Two HLA associations of comparable magnitudes were consistently observed between B*27:05 (median NT₅₀ Rochester cohort 48.9, p = 0.067; San Diego cohort 54.8, p = 0.047) and DPB1*04:01 (median NT₅₀ Rochester cohort 61.6, p < 0.001; San Diego cohort 70.8, p = 0.084) alleles and rubella virus-neutralizing antibody titers. Additional HLA alleles resulted in consistent effects on IL-6 production in both cohorts, but did not meet criteria for statistical significance. Our data suggest these HLA alleles play a role in rubella vaccine-induced immunity and provide the basis for future studies that may explain the mechanism(s) by which these HLA polymorphisms affect immune responses to rubella vaccine.     

Associations between single nucleotide polymorphisms and haplotypes in cytokine and cytokine receptor genes and immunity to measles vaccination

Identification of host genetic determinants of measles vaccine-induced immunity can be used to design better vaccines and ultimately predict immune responses to vaccination.We performed a comprehensive candidate gene association study across 801 genetic markers in 56 cytokine/cytokine receptor genes, in a racially diverse cohort of 745 schoolchildren after two doses of MMR vaccine. Using linear regression methodologies we examined associations between SNPs/haplotypes and measles virus-specific immunity.Forty-eight significant SNP associations with variations in neutralizing antibodies and measles-specific IFNγ Elispot responses were identified (p < 0.05). Our study replicated an important previously found association of a functional IL12B genetic variant rs3212227 with variations in measles-specific humoral immunity (p = 0.037). Similarly, two previously reported promoter IL10 and IL2 polymorphisms (rs1800890 and rs2069762) demonstrated associations with measles-specific cellular immunity in Caucasians (p ≤ 0.034). Multiple IL7R polymorphisms, including a non-synonymous functional SNP (rs6897932/Thr244Ile), were associated with humoral (p ≤ 0.024) and/or cellular (IFNγ Elispot, p ≤ 0.023) measles-specific immune responses in Caucasians, but not African-Americans. Haplotype level analysis confirmed the association of IL7R genetic variants with measles vaccine-induced immunity in the Caucasian group (global p-value = 0.003).Our results validate previous findings and identify new plausible genetic determinants, including IL7R polymorphisms, regulating measles vaccine-induced immunity in a race-specific manner.     

Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection

Background

Pertussis toxin (PT) is a specific virulence factor of Bordetella pertussis and it is included in all acellular pertussis vaccines (aP). Although immunity after infection seems to persist longer than that after vaccination, the exact mechanism(s) is not known. Primary aim of this study was to develop an ELISA method for measuring avidity index (AI) of IgG-anti-PT antibodies and to compare antibody responses after booster vaccination and infection. Secondary aim was to evaluate if the AI-ELISA has potential in the serodiagnosis of pertussis.

Material

Serum samples from a total of 409 subjects were included in the study. Paired sera were taken from 97 adolescents who received booster vaccine ten years ago (dTpa-004) and from 80 young adults who received a second booster dose ten years after the previous booster vaccine (dTpa-040). Thirty-two paired sera from culture-confirmed pertussis patients, 161 single sera from serologically diagnosed patients and 39 single sera from healthy controls were included. AI of IgG-anti-PT antibodies were determined with newly developed ELISA using diethylamine (DEA) as a bond breaking agent. The IgG-anti-PT antibodies were measured by standardized ELISA.

Results

A significant increase was found in antibody concentrations and AI between PRE and one month POST vaccination ten years ago [GMC for antibody: 7.9 IU/ml vs. 98.3 IU/ml (p = 0.0001); for AI: 40.4% vs. 56.1% (p = 0.0001)]. Similar result was observed after the second booster dose [GMC for antibody: 9.2 IU/ml vs. 92.4 IU/ml (p = 0.0001); for AI: 36.1% vs. 59.5% (p = 0.0001)] and between the first and second sera of culture-confirmed patients [GMC for antibody: 6.9 IU/ml vs. 285.1 IU/ml (p = 0.0001); for AI: 40.5% vs. 68.4% (p = 0.0001)]. Healthy controls showed lower levels of both antibodies and AI.

Conclusions

Our results suggest that there may be difference in quality and quantity of antibodies to PT after vaccination and after infection. Furthermore, AI could be a help for vaccine studies.     

Human leukocyte antigen associations with humoral and cellular immunity following a second dose of measles-containing vaccine: persistence, dampening, and extinction of associations found after a first dose

Previously we found human leukocyte antigen (HLA) associations with humoral immunity following a single dose of measles-containing vaccine. In this study, we sought to determine if HLA associations exist with humoral and cellular immunity following a second dose of measles-containing vaccine and if the associations we found with humoral immunity after the first dose persist following a second dose.We recruited a population-based sample of 346 schoolchildren, all who previously received two doses of a measles-containing vaccine. Molecular HLA classes I and II typing as well as humoral and cellular immune assays (measles-specific IgG antibody levels and lymphoproliferative response) were performed in these subjects.We found significant associations with class I HLA-B (p = 0.05) as well as class II HLA-DPB1 (p = 0.01) and -DPA1 (p = 0.03) genes for measles vaccine-induced antibody levels after the second dose. Similarly, we found significant associations with class II HLA-DQB1 (p = 0.05) and -DRB1 (p = 0.01) genes for measles-specific lymphoproliferation after the second dose.While we found HLA associations after the second dose that we previously found after the first dose of measles containing vaccine, fewer alleles had statistically significant associations, suggesting that the second dose had a dampening or extinguishing effect on the HLA associations. It appears that the second dose overcomes HLA restriction through an as yet unknown mechanism. Future studies of HLA associations should consider both the effect of dose and the role that subsequent doses might play on genetic associations found with the response to a first dose.     

Natural and vaccine-induced immunity to Neisseria meningitidis serogroup C in asplenic patients with β-thalassemia

Natural and vaccine-induced immunity to meningococcus C (MenC) was evaluated in asplenic adolescents and adults with β-thalassemia. At baseline 19.3% of patients and 22.8% age-matched controls had positive (>2 μg/ml) naturally acquired Men C- specific IgG antibodies; patients had a lower probability of having protective SBA compared to controls (OR = 21, p = 0.012). MenC conjugate vaccine (MCC) induced protective IgG concentrations in 63% of patients and 90.1% of controls. SBA increased significantly post vaccination and there were no differences between patients and controls; however patients had significantly lower IgG concentrations post vaccination compared to controls (4.52 vs 10.94 μg/ml, p < 0.001, respectively). A second dose of MCC given to 11 patients who had received MCC in the past induced higher IgG compared to primary response (p = 0.001). Naturally- and vaccine-induced immunity to MenC is impaired in asplenic β-thalassemics; a second dose of MCC improves vaccine immunogenicity and is essential for their optimal protection.     

Rubella seroprevalence in the first birth cohort reaching fertility age after 20 years of two dose universal vaccination policy in Israel

Background

A national program of a 2-dose universal childhood MMR vaccination policy has been in effect in Israel since 1988. As the 1988 birth cohort reached fertility age, questions regarding immunity against rubella were raised.

Objective

To assess the seroprevalence of rubella IgG antibodies among young Israeli adults born after 1987 in comparison to previous birth cohorts, in order to determine evidence based policy for prevention of rubella and congenital rubella syndrome.

Methods

We conducted a seroprevalence study of rubella IgG antibodies among 416 Israeli adults (42.5% females) born in 1988–1989, based on a representative sample of sera collected at age 18–19 upon recruitment to mandatory military service in 2007.

Results

In total, 87.7% were seropositive (>15 IU/ml) as compared with 84.8% in the 1999 recruitment (P = 0.26) and 93.4% in 1987 (P = 0.004). Yet there was a difference by gender. The proportion of seropositives among female young adults (92.7%) was significantly lower as compared to those measured in the 1999 (99.2%, P = 0.001) and 1987 (99.0%, P = 0.006) recruitments. The proportion of seropositives among males (84.1%) was significantly higher as compared to those measured in 1999 (73.0%, P < 0.001) but similar to those of 1987 (88.8%, P = 0.13). Females born in the FSU were found to be high risk groups as 11.5% were seronegative.

Conclusions

Our findings indicate that despite a successful program of congenital rubella syndrome prevention in Israel, there is a decline in seroprevalence among female young adults, especially immigrants from the FSU. A proactive catch-up program for females, especially for those of higher risk for susceptibility should be considered in Israel and in other countries.     

Association of HLA alleles with the responsiveness to hepatitis B virus vaccination in Korean infants

Hepatitis B virus (HBV) vaccination is the most effective means of countering HBV-related morbidity and mortality, and individuals who do not respond to vaccination (non-responders) are problematic. The aim of the present study was to investigate associations between HLA and responsiveness to HBV vaccine in Korean infants. A total of 944 healthy Korean infants 9–12 months old were enrolled, and HLA distribution was compared among subgroups in accordance with the response to HBV vaccination. The HLA distribution of the subjects was similar to known Korean population data and did not deviate from the HWE proportions. The alleles that showed positive associations with non-responsiveness (<10 mIU/mL) or low antibody titer (<100 mIU/mL) were HLA-A*33, B62, DRB1*04, and DRB1*07, while the alleles A*02 and DRB1*08 showed negative associations. Among these alleles, B62, DRB1*07 and DRB1*08(−) showed significant associations with a poor or decreased response to vaccination even after correction (OR = 1.83, 1.99, 5.63; p_c < 0.05) and also showed dose effects. After stratification by other associated alleles at different loci, B62 and DRB1*07 were independently associated with non-responsiveness, but A*02(−) and DRB1*08(–) lost their individual associations. The combined association of A*02(–)–DRB1*08(–) and B62–DRB1*08(–) was significant (OR = 25.2 and 24.5; p_c < 0.05). Although the hierarchy is not clear, we can assume the following: (i) B62 and DRB1*07 have independent effects, (ii) DRB1*08(–) has a very strong and synergic effect, and (iii) there is probability of a third factor controlling A*02(–) and DRB1*08(–) with an effect on non-responsiveness to HBV vaccination in Korean infants.     

The humoral immune response of hematopoietic stem cell transplantation recipients to AS03-adjuvanted A/California/7/2009 (H1N1)v-like virus vaccine during the 2009 pandemic

We evaluated the formation of hemagglutination-inhibition (HI) antibodies in response to vaccination of 55 allogeneic and 23 autologous hematopoietic stem cell transplantation (HSCT) recipients with 3.75 μg inactivated influenza A/California/7/2009 (H1N1)v-like virus adjuvanted with AS03, given towards the end of the 2009 influenza pandemic. The 78 HSCT recipients, aged 11-72 (median 50) years, were vaccinated 1-290 (median 27) months post-HSCT. Of the 55 allogeneic HSCT recipients, 50.9% received reduced intensity conditioning, 74.5% had a sibling donor, 67.2% had active graft-versus-host disease and 43.6% were on steroid therapy. At baseline, 14/78 (17.9%) had HI titers ≥1:40. Blood samples of 77 patients were available post-1st vaccination; of these, 34 (44.2%) patients had HI titers ≥1:40. Blood samples of 43 patients were available post-2nd vaccination; of these, 21 (48.8%) had HI titers ≥1:40. There was a significant increase in HI titers ≥1:40 from baseline to both post-1st and 2nd vaccinations (p < 0.001 each), and also from 1st to 2nd vaccination (p = 0.008). In seronegative (HI titers <1:10) patients, whose sera were available before, after one dose, and after 2 doses of vaccine, seroconversion (to ≥1:40) occurred in 4/24 (16.7%) after 1-dose and in a total of 10/24 (41.7%) after 2-dose vaccination (p = 0.031). Logistic regression analysis revealed that ≥1:40 HI titers were significantly associated with higher lymphocyte counts and higher HI baseline titers and, in allogeneic HSCT, with having a sibling donor and higher baseline titers. In conclusion, 2-dose vaccination with AS03-adjuvanted vaccine containing 3.75 μg antigen resulted in a statistically significant, yet limited, serological response. Therefore, additional precautions should be taken during influenza outbreaks.     

Association of HLA class II genes with clinical hyporesponsiveness to trivalent inactivated influenza vaccine in children

Background

The primary prevention measure for influenza infection has been the use of influenza vaccines. However, even when the vaccine and circulating strains are well-matched, some healthy children do not respond to the vaccine, likely due to a genetic basis for immune hyporesponsiveness. The primary objective of this study was to identify HLA class II genes associated with clinical hyporesponsiveness after trivalent inactivated influenza vaccine (TIV) in children.

Methods

We conducted a case–control study nested within a retrospective cohort of children that were screened at birth for HLA-DR,DQ genotypes by the Diabetes Autoimmunity Study in the Young (DAISY) and were subsequently followed for up to 8 years by Kaiser Permanente, Colorado (KPCO). Hyporesponsiveness was clinically defined as the occurrence of influenza or influenza-like illness (ILI) in peak influenza weeks in children fully vaccinated with TIV. Each child with clinical hyporesponse (n = 252) was matched to 4 randomly selected controls (n = 1006) by age and season. Children with clinical hyporesponse to TIV were identified using the Kaiser electronic clinical and immunization databases. Fully vaccinated children within the KPCO-DAISY cohort who did not have a diagnosis of ILI during the entire influenza season were eligible to be controls for that season. Class II HLA-DRB1 and HLA-DQB1 genes were the primary exposure variables. We used conditional logistic regression to calculate the matched odds ratios.

Results

In non-Hispanic white children, HLA-DR7/4,DQB1*0302 genotype was significantly associated (OR = 5.15; 95% CI = 1.94, 13.67; p = 0.001), while in Hispanic children, HLA-DRB1*15 or 16 allele (OR = 0.31; 95% CI = 0.14, 0.69; p = 0.004) and HLA-DR7/Y (DRB1*11, DRB1*13 and DRB1*14) genotype (OR = 5.84; 95% CI = 1.68, 20.28; p = 0.006) were significantly associated with clinical hyporesponsiveness after TIV.

Conclusions

HLA class II genes are associated with clinical hyporesponsiveness to TIV. This finding is important as it may help identify a group of children who are not protected by the commonly used TIV and may require alternative preventive strategies.     

Seroprevalence of measles and rubella antibodies in pregnant women Haiti, 2012

Background

Haiti had set a national goal to eliminate measles and rubella, as well as congenital rubella syndrome (CRS) by 2010. A 2007–2008 nationwide measles and rubella vaccination campaign targeting 1–19 years, however, reached only 79% of the target population. To assess whether population immunity was adequate to support elimination, we conducted a national serosurvey.

Methods

We systematically selected 740 serum specimens collected from pregnant women in a 2012 national antenatal HIV sentinel serosurvey across four age strata: 15–19, 20–24, 25–29 and 30–39 years. Sera were tested for measles and rubella specific immunoglobulin G antibodies (IgG) using commercial immunoassays. We classified sera as seropositive, seronegative or indeterminate per manufacturer's instructions, and analyzed seroprevalence according to age strata, and rural or urban residence. We assessed immunity by estimating antibody concentrations in international units per milliliter (IU/mL) for seropositive and indeterminate sera. Measles IgG concentrations >0.12 IU/mL and rubella IgG concentrations >10 IU/mL were considered clinically protective.

Results

Of 740 sera, 696 (94.1%) were seropositive and 20 (2.7%) were indeterminate for measles IgG; overall 716 (96.8%) sera had IgG concentrations >0.12 IU/mL. For rubella IgG, 691 (93.4%) sera were seropositive and 1 (0.1%) was indeterminate; a total of 687 (92.8%) had IgG concentrations >10 IU/mL. Measles seropositivity varied across age strata (p = 0.003); seropositivity increased from 88.6% among 15–19 year olds to 98.4% among 30–39 year olds (Cochran–Armitage trend test ≤ 0.0001). Rubella seropositivity did not differ across age strata. There were no statistically significant differences in measles or rubella seropositivity by urban versus rural residence.

Conclusion

Despite previous low vaccination coverage for measles, results from this serosurvey indicate high levels of measles and rubella seropositivity in pregnant women, and contribute to the evidence for measles, rubella and CRS elimination from Haiti by the target date.     

Rabies neutralizing antibody after 2 intradermal doses on days 0 and 21 for pre-exposure prophylaxis

Pre-exposure prophylaxis is recommended for people who will be exposed to rabies virus in the laboratory or who will contact with mammals. World Health Organization recommends 2 doses of a cell-culture rabies vaccine given 1 week apart, and a third booster dose given 2–3 weeks later. Neutralizing antibody response is virtually 100%, and the individual remains sensitized indefinitely. Intradermal pre-exposure regimen for rabies prophylaxis is more economical compared with the conventional intramuscular regimen in terms of vaccine volume. However, both regimens require three clinic visits. In order to reduce non-medical expenses such as transportation to the clinics and to increase compliance, the immunogenicity and safety of two-visit intradermal regimen for pre-exposure prophylaxis were studied. Fifty-five healthy subjects aged between 18 and 24 years were enrolled and divided into two groups. Group A (n = 39) received 0.1 ml of purified Vero cell rabies vaccine (PVRV; Sanofi Pasteur, Lyon, France; Lot no. Z0996 with an antigenic value of 4.8 IU/0.5 ml vial) intradermally each at two sites on days 0 and 21. Group B (n = 16) received 0.5 ml of PVRV intramuscularly on days 0, 7 and 21, as conventional intramuscular regimen for pre-exposure prophylaxis. Rabies neutralizing antibody (Nab) titers were measured on days 0, 35, 365 and 379 (14 days after simulated post-exposure booster vaccination). All subjects from two groups had Nab titers ≥0.5 IU/ml on day 35. In addition, the difference between geometric mean titers for group A (4.51 IU/ml; range of Nab titers 1.69–13.0 IU/ml) and group B (6.74 IU/ml; range of Nab titers 2.20–14.23 IU/ml) on day 35 was not statistically significant (p > 0.05). One year after pre-exposure vaccination, all subjects in both groups received simulated post-exposure booster vaccination with 0.1 ml of PVRV ID on days 0 and 3 (day 365 and day 368 after pre-exposure vaccination). After simulated booster vaccinations with 0.1 ml PVRV ID on days 0 and 3, all subjects in groups A (GMT 14.38 IU/ml; range 2.99–308.44 IU/ml) and in group B (GMT 14.06 IU/ml; range 3.12–62.09 IU/ml) had rabies Nab titers ≥0.5 IU/ml on day 14 post-booster (p > 0.05). Mild local adverse events such as pain at injection site, pruritus and erythema were observed. Our study indicated that 2-site intradermal pre-exposure regimen on days 0 and 21 with 0.1 ml of cell-culture rabies vaccine is safe and immunogenic as the conventional intramuscular regimen.     

Genetic polymorphisms in host antiviral genes: associations with humoral and cellular immunity to measles vaccine

Host antiviral genes are important regulators of antiviral immunity and plausible genetic determinants of immune response heterogeneity after vaccination. We genotyped and analyzed 307 common candidate tagSNPs from 12 antiviral genes in a cohort of 745 schoolchildren immunized with two doses of measles-mumps-rubella (MMR) vaccine. Associations between SNPs/haplotypes and measles virus-specific immune outcomes were assessed using linear regression methodologies in Caucasians and African-Americans.Genetic variants within the DDX58/RIG-I gene, including a coding polymorphism (rs3205166/Val800Val), were associated as single-SNPs (p ≤ 0.017; although these SNPs did not remain significant after correction for false discovery rate/FDR) and in haplotype-level analysis, with measles-specific antibody variations in Caucasians (haplotype allele p-value = 0.021; haplotype global p-value = 0.076). Four DDX58 polymorphisms, in high LD, demonstrated also associations (after correction for FDR) with variations in both measles-specific IFN-γ and IL-2 secretion in Caucasians (p ≤ 0.001, q = 0.193). Two intronic OAS1 polymorphisms, including the functional OAS1 SNP rs10774671 (p = 0.003), demonstrated evidence of association with a significant allele-dose-related increase in neutralizing antibody levels in African-Americans. Genotype and haplotype-level associations demonstrated the role of ADAR genetic variants, including a non-synonymous SNP (rs2229857/Arg384Lys; p = 0.01), in regulating measles virus-specific IFN-γ Elispot responses in Caucasians (haplotype global p-value = 0.017). After correction for FDR, 15 single-SNP associations (11 SNPs in Caucasians and 4 SNPs in African-Americans) still remained significant at the q-value < 0.20.In conclusion, our findings strongly point to genetic variants/genes, involved in antiviral sensing and antiviral control, as critical determinants, differentially modulating the adaptive immune responses to live attenuated measles vaccine in Caucasians and African-Americans.     

Consistency of HLA associations between two independent measles vaccine cohorts: a replication study

Associations between HLA genotypes and measles vaccine humoral and cellular immune responses were examined to better understand immunogenetic drivers of vaccine response. Two independent study cohorts of healthy schoolchildren were examined: cohort one, 346 children between 12 and 18 years of age; and cohort two, 388 children between 11 and 19 years of age. All received two age-appropriate doses of measles-containing vaccine. The purpose of this study was to identify and replicate associations between HLA genes and immune responses following measles vaccination found in our first cohort. Associations of comparable magnitudes and with similar p-values were observed between B*3503 (1st cohort p=0.01; 2nd cohort p=0.07), DQA1*0201 (1st cohort p=0.03; 2nd cohort p=0.03), DQB1*0303 (1st cohort p=0.10; 2 cohort p=0.02), DQB1*0602 (1st cohort p=0.07; 2nd cohort p=0.10), and DRB1*0701 (1st cohort p=0.03; 2nd cohort p=0.07) alleles and measles-specific antibody levels. Suggestive, yet consistent, associations were observed between the B7 (1st cohort p=0.01; 2nd cohort p=0.08) supertype and higher measles antibody levels in both cohorts. Also, in both cohorts, the B*0801 and DRB1*0301 alleles, C*0802 and DPA1*0202 alleles, and DRB1*1303 alleles displayed consistent associations with variations in IFN-γ, IL-2 and IL-10 secretion, respectively. This study emphasizes the importance of replicating HLA associations with measles vaccine-induced humoral and cellular immune responses and increases confidence in the results. These data will inform strategies for functional studies and novel vaccine development, including epitope-based measles vaccines. This is the first HLA association replication study with measles vaccine-specific immune responses to date.     

The relationship between concentration of specific antibody at birth and subsequent response to primary immunization

Background and aims

Trans-placentally acquired antibodies can protect infants from infection in the first months of life. However, high concentrations of antibody at birth may impact the infant's own immune response to primary immunization. We examine the relationship between concentration of specific antibody to Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid and pneumococcal antigens at birth and following primary immunization.

Methods

Healthy mother–infant pairs were recruited from a UK maternity unit. Peripheral blood samples were obtained at birth and 4 weeks after primary immunization. Specific antibody concentrations were determined using enzyme-linked immunosorbent assays. Pertussis antibody concentrations >50 IU/ml, Tetanus antibody levels >0.1 IU/ml and Hib antibody levels >0.15 mg/l were regarded as protective.

Results

Following primary immunization, 35/36 (97%) infants had specific antibody concentrations associated with protection against Hib, 32/36 (89%) against pertussis and 36/36 (100%) against tetanus. Concentrations of all specific antibodies were significantly higher than at birth (p < 0.0001), except anti-tetanus toxoid, p = 0.41. However, there was an inverse correlation between infant antibody concentration at birth and fold-increase in antibody concentration post-immunization for tetanus: r_s −0.86 (95%CI −0.93 to −0.74), p < 0.0001; pneumococcus: r_s −0.82 (95% CI −0.91 to −0.67), p < 0.0001; pertussis: r_s −0.77 (95% CI −0.89 to −0.58), p < 0.0001 and Hib: r_s −0.66 (95%CI −0.82 to −0.42), p < 0.0001. The highest concentrations of specific IgG at birth were associated with lower concentrations post-immunization for tetanus (p = 0.009) and pneumococcus (p = 0.03). This association was not observed for Hib (p = 0.88) or pertussis (p = 0.14).

Conclusion

Higher antibody concentration at birth appeared to inhibit the response to infant immunization for tetanus and pneumococcus; the effect was less marked for Hib and pertussis. However, the majority of infants achieved high antibody levels post-immunization. This supports maternal immunization, as high levels of maternally derived antibody at birth may not inhibit infants’ immunization responses in a clinically relevant manner.     

Repeat revaccination with 23-valent pneumococcal polysaccharide vaccine among adults aged 55-74 years living in Alaska: no evidence of hyporesponsiveness

Background

Older adults are at highest risk of invasive pneumococcal disease (IPD) and are recommended to receive vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). Antibody concentrations decline following vaccination. We evaluated the immunogenicity and reactogenicity of revaccination and repeat revaccination.

Methods

Adults aged 55-74 years were vaccinated with a 1st to 4th dose of PPV23. Participants were eligible for revaccination if a minimum of 6 years had passed since their last dose of PPV23. Blood collected on the day of vaccination and 30 days later was analyzed by ELISA for IgG to five serotypes. Functional antibody activity was measured using an opsonophagocytic killing (OPK) assay. Reactions to vaccination were documented.

Results

Subjects were vaccinated with a 1st dose (n = 123), 2nd dose (n = 121), or 3rd or 4th dose (n = 71) of PPV23. The post-vaccination IgG geometric mean concentrations (GMCs) were similar among first-time vaccinees and re-vaccinees for all serotypes with the exception of a lower GMC for serotype 1 in re-vaccinees. The post-vaccination OPK geometric mean titers (GMTs) were similar among first-time vaccinees and re-vaccinees with the exception of a higher GMT for serotype 6B in re-vaccinees. Compared to first-time vaccinees, re-vaccinees reported more joint pain (p = 0.004), fatigue (p = 0.019), headache (p = 0.014), swelling (p = 0.006), and moderate limitation in arm movement (p = 0.025).

Conclusions

Repeat revaccination with PPV23, administered 6 or more years after the prior dose, was immunogenic and generally well tolerated.     

Examining the relationship between brominated flame retardants (BFR) exposure and changes of thyroid hormone levels around e-waste dismantling sites

Brominated flame retardants (BFRs) released from e-waste related activities may affect the health of local people. Assessing the impact of e-waste exposure during recycling and dismantling activities on local people's thyroid hormone levels is an area of ongoing research. During November and December 2008, the process of e-waste recycling and dismantling was investigated, and 236 occupation-exposed people and 89 non-occupation-exposed people approximate to the e-waste recycling sites were surveyed; their thyroid hormone levels (THs), thyrotropins (TSH) and BFRs levels in serum were assayed. Multiple regression models were constructed to analyze the changes of serum THs and TSH in the people living in the exposure area (exposure group) and the people in the control group. Covariates known to be or likely to be associated with THs, TSH and BFRs levels were analyzed. Lower level of Triiodothyronine (T₃) in both occupation-exposed and non-occupation-exposed group were observed (p < 0.01), when compared with the control group, and the same trend was obtained for free triiodothyronine (fT₃) and free thyroxine (fT4) (p < 0.01). However, no significant difference in thyroxine (T₄) was found between the two groups. The level of TSH in the e-waste recycling occupational-exposed group ranged from 0.00 to 5.00 μIU/ml with a mean of 1.26 μIU/ml, whereas the level of TSH in the control group was from 0.03 to 5.54 μIU/ml with a mean of 1.57 μIU/ml. This study revealed that people having worked on e-waste recycling and dismantling had significantly lower TSH compared with the control group (p < 0.01). Moreover, the level of BDE-205 is positively associated with the level of T4, as confirmed by the linear regression model (unstandardized regression coefficient, beta = 0.25, ρ = 0.001) and a weaker positive relation was also found between the levels of BDE-126 and T4. Meanwhile, a weak negative relation was found between the levels of PBB 103 and T3, and between the levels of fT3 and fT4. These results suggest that exposure to BFRs released from primitive e-waste handling may contribute to the changes of THs and TSH levels.     

Long-term safety and serologic response to measles, mumps, and rubella vaccination in HIV-1 infected adults

We analyzed HIV viral load (VL) and CD4 count changes, and antibody responses following MMR vaccination of individuals in the U.S. Military HIV Natural History Study cohort. Cases receiving at least one dose of MMR vaccine after HIV diagnosis were matched 1:2 to HIV-positive controls not receiving the vaccine. Baseline was defined as time of vaccination for cases and indexed and matched to the time post-HIV diagnosis for controls. Changes in CD4 count and VL at 6, 12, 18 and 24 months were compared between cases and controls using a general linear model. Available sera from cases were tested for MMR seropositivity at baseline and post-vaccination at 6, 12, 18, and 24 months. Overall mean CD4 count change from baseline through 24 months was 20 (±23) cells/μL greater for cases than controls (p = 0.39). Similar non-significant changes in CD4 cell count were seen in the subset of those not on HAART at baseline. VL changes were small and similar between groups (mean differential change −0.04 (±0.18) log₁₀ copies/mL; p = 0.84). Of 21 vaccinated participants with baseline serologic testing, 14 (67%) were reactive to measles, 19 (91%) to mumps, and 20 (95%) to rubella. Three (43%) of 7 participants nonreactive to measles developed measles IgG; for mumps, 1 (50%) of 2 developed mumps IgG; for rubella, 1 (100%) developed rubella IgG. MMR vaccination did not result in detrimental immunologic or virologic changes through 24 months post-vaccination.     

Effect of recurrent invasive pneumococcal disease on serum anti-pneumolysin IgG titres in HIV infected adults

We measured serum anti-pneumolysin IgG concentrations in a prospective cohort of 34 HIV infected adults who developed recurrent pneumococcal bacteraemia, and compared baseline levels with HIV positive and HIV negative control subjects that remained free of pneumococcal disease. Anti-pneumolysin concentrations in HIV positive cases and controls were higher compared to HIV negative controls. There was no significant difference in levels between HIV positive subjects who did and did not subsequently develop pneumococcal bacteraemia (geometric means 849.1 U/ml vs. 564.6 U/ml, p = 0.059). Anti-pneumolysin IgG titres before, and after the recurrent episode of pneumococcal bacteraemia did not differ significantly (p = 0.95). High levels of anti-pneumolysin IgG do not predict protection from invasive pneumococcal disease or indicate that an effective immune response has occurred in HIV infected patients.     

Immunogenicity and tolerability of an inactivated and adjuvanted pandemic H1N1 influenza vaccine, in HIV-1-infected patients

We evaluated the efficacy and tolerability of a single dose of the split virion AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in 84 HIV-1 infected individuals. Antibody titers were determined by hemagglutination inhibition assay and by microneutralization. Vaccine was well tolerated. At 21 days post vaccination, 56 (67%) patients had seroconverted. There was no correlation between baseline CD4 cell count (p = 0.539) or HIV viral load (p = 0.381) and immune response. Other vaccine strategies should be evaluated in this HIV population, to improve response rates.     

Effect of probiotic supplementation in the first 6 months of life on specific antibody responses to infant Hepatitis B vaccination

Probiotics have been shown to enhance specific immune responses to vaccines. We aim to assess the effect of probiotic supplementation on specific IgG antibody responses to Hepatitis B (HepB) vaccination in infants. Compared to controls, probiotic supplementation improved HepB surface antibody responses in subjects receiving monovalent doses of HepB vaccine at 0, 1 month and a DTPa–HepB combination vaccine at 6 months [placebo (n = 28): 187.97 (180.70–195.24), probiotic (n = 29): 345.70 (339.41–351.99) mIU/ml] (p = 0.069), but not those who received 3 monovalent doses [placebo (n = 68): 302.34 (296.31–308.37), probiotic (n = 77): 302.06 (296.31–307.81) mIU/ml] (p = 0.996). Probiotics may enhance specific antibody responses in infants receiving certain Hepatitis B vaccine schedules.