Immunological memory and nasopharyngeal carriage in 4-year-old children previously primed and boosted with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) with or without concomitant prophylactic paracetamol

Background

Prophylactic paracetamol (PP) was previously shown to reduce primary and booster antibody responses against the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). This study further evaluated the effect of PP on antibody persistence, immunological memory and nasopharyngeal carriage (NPC).

Methods

Two hundred and twenty children previously primed (3 doses, NCT00370318) and boosted (NCT00496015) with PHiD-CV with (PP group) or without (NPP group) prophylactic paracetamol administration received one PHiD-CV dose in their fourth year of life to assess the induction of immunological memory following previous immunisations. A control group of age-matched unprimed children enrolled in study NCT00496015 received an investigational tetravalent Neisseria meningitidis serogroups A, C, W-135, Y tetanus toxoid-conjugate vaccine, and thus remained unprimed for pneumococcal vaccination. Of these, 223 unprimed children received in the present study at least one PHiD-CV dose of a 2-dose catch-up regimen, which was relevant as control for assessment of immunological memory in PHiD-CV primed children.

Results

Induction of immunological memory was shown irrespective of PP administration at primary and booster vaccination. Antibody geometric mean concentrations were lower in the PP group for serotypes 1, 4, 7F and 9V. Opsonophagocytic titres did not differ significantly between PP and NPP groups. Previous use of PP seemed to have only a minor impact on kinetics of antibody persistence. Reduced NPC of vaccine pneumococcal serotypes and trends towards increased NPC of non-vaccine and non-cross-reactive serotypes were seen in primed groups versus the control group, with no obvious differences between PP and NPP groups.

Conclusion

Regardless of whether previous PHiD-CV vaccination was given with or without PP, induction of immunological memory and persistence of PHiD-CV's impact on carriage was seen until at least 28 months post-booster vaccination. Our study results therefore suggest that the lower immune responses after primary and booster vaccination with PP are of transient nature.     

Girls may have lower levels of maternal measles antibodies and higher risk of subclinical measles infection before the age of measles vaccination

Background

Previous studies have suggested that girls may have lower maternal measles antibody levels than boys. Girls might therefore be more likely to contract measles infection before the normal age of measles vaccination at 9 months of age.

Methods

In connection with a clinical trial of different measles vaccination strategies, we collected pre-measles vaccination blood samples at 4.5 months of age from two subgroups of children. Samples from these children were used to assess possible differences in maternal antibody levels for boys and girls. At 9 months of age another subgroup of children was sampled before the normal measles vaccination; these samples were used to assess the frequency of subclinical measles infection among boys and girls.

Results

We determined measles-specific antibody levels for 812 children at 4.5 months of age and for 896 children at 9 months of age. At 4.5 months of age girls were less likely to have protective maternal antibody levels, the male–female ratio for protective antibody level being 1.23 (1.00–1.51). Among children sampled at 9 months of age, girls were more likely to have protective levels, the female–male ratio for having protective antibody levels being 1.65 (0.98–2.78) (p = 0.054) and the geometric mean titre was significantly higher for girls (p = 0.007). Children who lived in houses with known measles cases were more likely to have protective levels at 9 months of age even though they had not reported measles infection. Since we had excluded children with known measles infection, girls may have been more likely to have had subclinical measles infection. Combining clinical and possible subclinical measles infection, girls tended to be more likely than boys to contract measles infection before 9 months of age, the RR being 1.36 (0.97–1.90).

Conclusions

Girls lost maternal measles antibodies more rapidly than boys and well before 9 months of age. They may be more likely to contract subclinical measles infection before the current age of measles vaccination.     

Safety and immunogenicity of live-attenuated Japanese encephalitis SA 14-14-2 vaccine co-administered with measles vaccine in 9-month-old infants in Sri Lanka

Introduction

To facilitate introduction of live attenuated SA 14-14-2 Japanese encephalitis vaccine (LJEV) into the National Immunization Programme of Sri Lanka, we evaluated the safety and immunogenicity of co-administration of LJEV and measles vaccine at 9 months of age. Serum immune responses were evaluated post-vaccination on days 28, 180, and 365 using JE neutralization test and anti-measles IgG ELISA.

Results

278 infants received one dose of LJEV and measles vaccine. Of these, 257 were eligible for the per-protocol analysis. On Day 0, 14 infants (5.5%) were seropositive for JE, but none were seropositive for measles. At Day 28, seropositivity rates were 90.7% (95% CI, 86.4–93.9%) for JE and 84.8% (95% CI, 79.8–89.0%) for measles. The geometric mean titer for JE neutralizing antibodies was 111 (95% CI, 90–135), and the geometric mean concentration (GMC) for anti-measles IgG was 375 mIU/mL (95% CI, 351–400 mIU/mL). Over the next year, JE neutralizing antibody responses declined only slightly, with seropositivity at 87.4% (95% CI, 82.6–91.2%) at Day 365. In contrast, measles antibody levels continued to increase over time. Seropositivity for anti-measles IgG reached 97.2% (95% CI, 94.4–98.9%) at Day 365, and the GMC rose to 1202 mIU/mL (95% CI, 1077–1341 mIU/mL). Co-administration of LJEV and measles vaccine was also safe. Most adverse reactions were mild, and no serious adverse events were related to study vaccinations.

Conclusion

The safety and immunogenicity of LJEV co-administered with measles vaccine in Sri Lankan infants is similar to that seen in other populations, and our results support use of LJEV at 9 months of age. Live SA 14-14-2 vaccine is now prequalified by the WHO for use in infants in Asia, and other countries may wish to introduce LJEV to combat this devastating disease.     

Early loss of measles antibodies after MMR vaccine among HIV-infected adults receiving HAART

Objective

: The objective of the study was to evaluate the immune response to measles vaccine of HIV-infected adults in comparison to HIV non-infected adults.

Design

We conducted a cross-sectional study to identify adults lacking measles antibodies. 26 HIV-infected patients and 22 controls found to be measles seronegative in the cross-sectional study, received the MMR vaccine. We prospectively followed patients and measured measles antibodies, and cellular proliferative responses against measles antigens. We registered all adverse events at baseline, 3 and 12 months after vaccination.

Methods

We determined measles antibodies by ELISA and cellular proliferative response in PBMC's at baseline, and repeated measurements at 3 and 12 months after vaccination.

Results

The humoral immune response to the vaccine between HIV-infected adults and the HIV-uninfected group was not statistically different at 3 months (81% vs. 86% respectively). One year after vaccination, a higher proportion of HIV-infected adults had lost measles antibodies in contrast to controls. The cellular response was not statistically different between the groups at baseline, 3 and 12 months after immunization despite the waning of antibodies at 12 months. No severe adverse events were observed. Most patients were receiving HAART and had a mean CD4+ cell count of 496 cells/mL.

Conclusions

The initial humoral immune response to measles vaccine was not different between HIV-infected adults and HIV-uninfected adults. However, HIV-infected adults have a rapid decline of measles antibodies despite their high CD4+ cell count and sustained cellular proliferative response.     

A probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials

Background

Influenza vaccination is recommended for the elderly in many countries, but immune responses are weaker compared to younger adults.

Objective

To investigate the impact of daily consumption of a probiotic dairy drink on the immune response to influenza vaccination in an elderly population of healthy volunteers over 70 years of age.

Design

Two randomised, multicentre, double-blind, controlled studies were conducted during two vaccination seasons in 2005–2006 (pilot) and 2006–2007 (confirmatory). Eighty-six and 222 elderly volunteers consumed either a fermented dairy drink, containing the probiotic strain Lactobacillus casei DN-114 001 and yoghurt ferments (Actimel^®), or a non-fermented control dairy product twice daily for a period of 7 weeks (pilot) or 13 weeks (confirmatory). Vaccination occurred after 4 weeks of product consumption. Geometric mean antibody titres (GMT) against the 3 viral strains composing the vaccine (H1N1, H3N2, and B) were measured at several time intervals post-vaccination by haemagglutination inhibition test.

Results

In the pilot study, the influenza-specific antibody titres increased after vaccination, being consistently higher in the probiotic product group compared to the control group under product consumption. Similarly, in the confirmatory study, titres against the B strain increased significantly more in the probiotic group than in the control group at 3, 6 and 9 weeks post-vaccination under product consumption (p = 0.020). Significant differences in seroconversion between the groups by intended to treat analysis were still found 5 months after vaccination. Similar GMT results were observed for the H3N2 strain and H1N1 strain, confirming the results of the pilot study.

Conclusion

These studies demonstrate that daily consumption of this particular probiotic product increased relevant specific antibody responses to influenza vaccination in individuals of over 70 years of age and may therefore provide a health benefit in this population.     

A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects

Background

Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations.

Methods

This randomised trial enrolled 410 healthy adult (18–60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 μg or 7.5 μg antigen, adjuvanted with half the standard dose, or a standard dose of MF59^® (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 μg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated.

Results

All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 μg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 μg and 7.5 μg antigen were optimal for the adult and elderly populations, respectively.

Conclusions

These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 μg or 7.5 μg formulations) and healthy elderly (7.5 μg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres.

Trial registration

www.clinicaltrials.gov (NCT00971906).     

Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics

Objective

Respiratory infections are major triggers of exacerbations in preschool asthma. Many countries’ guidelines recommend immunization against pneumococci for patients suffering from chronic airway disease. Beyond infancy, however, data on the immunogenicity and safety are scarce. Also, the interval between priming and booster is a matter of debate.

Patients and Methods

Seventy preschool asthmatics (2–5-year-old; mild to moderate asthma) underwent sequential immunization: one dose of seven-valent pneumococcal conjugate vaccine (PCV-7) followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23). We randomly assigned half of the vaccinees to receive PPV-23 eight weeks after PCV-7 (group A), and the rest to a 10-month interval (group B). Pneumococcal antibody concentrations to serotype 4, 5, 6B, 7, 9V, 14, 18c, 19F and 23F were determined initially, after two and 12 months after PCV-7. Local and systemic reactions to each vaccine were recorded.

Results

Initially, depending on the serotype, up to 79.4% (group A) or 80.4% (group B) individuals did not reach the protective antibody threshold of 0.35 μg/ml. Sequential pneumococcal immunization was immunogenic in preschool asthmatics, inducing protection in the majority of our children. Subjects boostered after eight weeks had significantly lower antibody levels than those boostered after 10 months. Local and systemic adverse events were mild in character and self-limiting.

Conclusions

Although both sequential pneumococcal vaccine regimens were safe and immunogenic among preschool asthmatics, immunogenicity was higher when the booster was given after 10 months.     

Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations

Background and aims

Serogroup A, C, W-135 and Y meningococcal (MenACWY) conjugate vaccines are recommended for routine adolescent immunisation in the United States and Canada. We evaluated the persistence of bactericidal antibodies through early childhood, following infant immunisation with varying schedules of MenACWY-CRM₁₉₇ vaccine.

Methods

UK and Canadian infants were immunised with 2–3 doses of MenACWY-CRM₁₉₇ or 2 doses of serogroup C meningococcal (MenC) conjugate vaccine, and either MenACWY-CRM₁₉₇, 1/5 dose of MenACWY polysaccharide vaccine or no booster at 12 months. Control groups recruited at 60 months had received country-specific infant doses of MenC conjugate vaccine. hSBA titres were measured in participants at 40 and 60 months of age.

Results

382 children were enrolled in 12 groups (22–40 per group). By age 60 months, 3–11% of children primed and boosted with MenACWY-CRM₁₉₇ had hSBA titres ≥ 1:8 against serogroup A, 14–45% against serogroup C, 57–85% against serogroup W-135 and 42–71% against serogroup Y. Children primed with MenC and boosted with MenACWY-CRM₁₉₇ had similar results, except for serogroup C (59%). In age-matched controls administered MenC vaccine at 2, 3, and 4 months (UK), 2 and 12 months or 12 months only (Canada), percentages with hSBA titres ≥ 1:8 were 0–3%, 29–53%, 34–36% and 10–29% against serogroups A, C, W-135 and Y respectively.

Conclusions

Serogroup-specific bactericidal antibody wane following infant immunisation with MenACWY-CRM₁₉₇, most markedly against serogroup A. Best persistence against serogroup C is observed with MenC conjugate vaccine priming and MenACWY-CRM₁₉₇ at 12 months, compared to schedules using only MenACWY-CRM₁₉₇, with the potential for providing broader protection compared to monovalent MenC vaccines alone.     

Immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine administered concomitantly with measles, mumps, rubella, varicella vaccine in healthy toddlers

Background

Invasive meningococcal disease can have devastating outcomes, especially in high-risk groups such as infants. As infants are recommended to receive multiple vaccines during a single office visit, this phase 3 study assessed the safety and immune response to MenACWY-CRM at alternative visits in older infants and concomitant use with measles, mumps, rubella, varicella vaccine (MMRV) at 12 months of age.

Methods

Two age groups were concurrently enrolled: 7- to 9-month-old infants who received 2 doses of MenACWY-CRM at 7–9 and 12 months and were randomized 1:1 to receive MenACWY-CRM with or without MMRV at 12 months, and 12-month-old infants who received MMRV only at12 months. Using predefined non-inferiority criteria, immune responses to the antigens in MMRV were compared between those who did and did not receive MenACWY-CRM; immune responses to MenACWY-CRM as measured by the percentage of subjects with human serum bactericidal activity (hSBA) titers ≥ 8, were compared between those who did and did not receive concomitant MMRV. Adequacy of the immune response to 2 doses of MenACWY-CRM administered at 7–9 and 12 months was also assessed. Local and systemic reactions, adverse events resulting in withdrawal or requiring medical attention and serious adverse events were monitored.

Results

Concomitant administration of MMRV with MenACWY-CRM did not affect the immune response to either vaccine. The 2-dose series of MenACWY-CRM induced adequate immune response to all 4 serogroups. No increased reactogenicity was observed with MenACWY-CRM + MMRV compared with MMRV alone, and there were no study-related serious adverse events.

Conclusions

Concomitant administration of MenACWY-CRM with MMRV vaccinations at 12 months was well-tolerated, without safety concerns. Robust immune responses to all components of both vaccines were produced and all criteria for non-inferiority were met, supporting the use of a 2-dose regimen of MenACWY-CRM in this age group.     

A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children

Objectives

To evaluate an investigational, fully liquid hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-hepatitis B-Haemophilus influenzae type b (DTaP-IPV-Hep B-PRP-T: Hexaxim™) vaccine for primary and booster vaccination of healthy children in Mexico.

Methods

Infants (N = 1189) were randomized to receive one of three lots of the DTaP-IPV-Hep B-PRP-T vaccine or a licensed hexavalent control vaccine (Infanrix™ hexa) for primary vaccination at 2, 4 and 6 months. All participants who completed the primary series and agreed to participate in the booster part of the study received a dose of the investigational vaccine at 15–18 months of age. Validated serological assays and parental reports were used to assess immunogenicity and safety, respectively.

Results

Post-primary vaccination, ≥95.8% of participants in both the DTaP-IPV-Hep B-PRP-T and control groups were seroprotected (SP) against diphtheria, tetanus, poliovirus, hepatitis B and PRP, or had seroconverted (SC) to the pertussis toxin (PT) and filamentous hemagglutinin (FHA) pertussis antigens. The SP/SC rates induced by the three DTaP-IPV-Hep B-PRP-T lots were equivalent. No differences in SP/SC rates were observed between the pooled lots of investigational vaccine and the control vaccine. Antibody persistence at 15–18 months was comparable between groups, with strong increases in all antibody concentrations post-DTaP-IPV-Hep B-PRP-T booster. Both vaccines were well tolerated for primary vaccination, as was the booster dose of DTaP-IPV-Hep B-PRP-T.

Conclusion

These study findings confirm the suitability of the combined, fully liquid DTaP-IPV-Hep B-PRP-T vaccine for inclusion in routine childhood vaccination schedules.     

Rubella control in Papua New Guinea: Age-specific immunity informs strategies for introduction of rubella vaccine

Aim

To determine the age specific immunity profile for rubella from three discrete study populations in Papua New Guinea, and to inform policy regarding the possible introduction of rubella vaccine.

Background

In 2005, the Western Pacific Region (WPR), of which Papua New Guinea (PNG) is a member state, declared the goal of regional measles elimination by 2012. Recently, WPR has incorporated an accelerated control goal for rubella and congenital rubella syndrome (CRS). PNG currently recommends two doses of measles vaccination at 6 and 9 months of age with a monovalent measles vaccine, which does not include rubella vaccine.

Methods

Convenience samples were collected from 1326 eligible participants in PNG and assessed for rubella immunity using the Dade Behring Enzygnost™ Anti-Rubella-Virus enzyme immunoassay. Nearly 34% were collected during an age stratified prospective survey of febrile patients in Madang Province; approximately 49% were collected from women of childbearing age in East Sepik and Milne Bay Provinces. Remaining specimens were collected from 6 to 7-month-old infants in Port Moresby prior to receiving the first dose of measles vaccine.

Findings

Of all samples tested, 65.2% (95% confidence interval (CI): 62.6–67.8) had evidence of immunity to rubella infection. Of women more than 15 years of age, 91.6% (95% CI: 89.4–93.5) were immune. The force of infection was highest between 5 and 19 years of age.

Conclusions

Although a population-based sample was not used, our multi-centre study of the population immunity profile suggests that immunity against rubella is extremely high in most women of childbearing age, but women who become pregnant at an early age may be at high risk of rubella infection during pregnancy and potential delivery of an infant with CRS. Routine measles vaccine coverage, a proxy for measles-rubella vaccine coverage, as measured in recently published studies, is well below the WHO target of 80% coverage. Introduction of a child or infant dose of rubella vaccine requires caution and further study.     

An observer-blind,randomized, multi-center trial assessing long-term safety and immunogenicity of AS03-adjuvanted or unadjuvanted H1N1/2009 influenza vaccines in children 10–17 years of age

Background

Vaccination is an effective strategy to prevent influenza. This observer-blind, randomized study in children 10–17 years of age assessed whether the hemagglutination inhibition (HI) antibody responses elicited by H1N1/2009 vaccines adjuvanted with AS03 (an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion) or without adjuvant, met the European regulatory immunogenicity criteria at Days 21 and 182.

Methods

Three hundred and ten healthy children were randomized (3:3:3:5) to receive one dose of 3.75 μg hemagglutinin (HA) AS03_A-adjuvanted vaccine, one or two doses of 1.9 μg HA AS03_B-adjuvanted vaccine, or one dose of 15 μg HA pandemic vaccine. All children received a booster dose of the allocated vaccine at Day 182. Serum samples were tested for HI antibody response at Days 21, 42, 182 and 189.

Results

All vaccination regimens elicited HI antibody responses that met the European regulatory criteria at Days 21 and 42. HI antibody responses fulfilling European regulatory criteria were still observed six months after the first vaccine dose in all study vaccines groups. Two doses of 1.9 μg HA AS03_B-adjuvanted vaccine elicited the strongest HI antibody response throughout the study. The non-adjuvanted 15 μg HA vaccine elicited a lower HI antibody response than the AS03-adjuvanted vaccines. At Day 189, the European regulatory criteria were met for all vaccines with baseline HI antibody titers as reference. An anamnestic response for all vaccines was suggested at Day 189, based on the rapid increase in HI antibody geometric mean titers (1.5–2.5-fold increase). Injection site reactogenicity was higher following the AS03-adjuvanted vaccines compared with the non-adjuvanted vaccine. No safety concerns were identified for any study vaccine.

Conclusion

All study vaccines elicited HI antibody responses that persisted at purported protective levels through six months after vaccination and fulfilled the European regulatory criteria.     

A randomised, single-blind, dose-range study to assess the immunogenicity and safety of a cell-culture-derived A/H1N1 influenza vaccine in adult and elderly populations

Background

Modern cell-culture production techniques and the use of adjuvants helps to ensure that the global demand for pandemic influenza vaccine can be met. This study aimed to assess the immunogenicty and safety profiles of various cell-culture-derived A/H1N1 pandemic vaccine formulations in healthy adult and elderly subjects.

Methods

Adult (18–60 years) subjects (n = 544) received vaccine either containing 3.75 μg of antigen with half the standard dose of MF59^® (Novartis Vaccines and Diagnostics) adjuvant, 7.5 μg antigen with a full dose of MF59, or a non-adjuvanted vaccine containing 15 μg of antigen. Elderly (≥61 years) subjects (n = 268) received either the 3.75 μg or 7.5 μg adjuvanted formulations. Two priming vaccine doses were administered 3 weeks apart, followed by a single booster dose of seasonal influenza vaccine 1 year later. Immunogenicity was assessed 3 weeks after each vaccination. The safety profile of each formulation was evaluated throughout the study.

Results

A single primary dose of each A/H1N1 vaccine formulation was sufficient to meet all three European (CHMP) licensure criteria for pandemic influenza vaccines in adult subjects. Two licensure criteria were met after one vaccine dose in elderly subjects; two primary doses were required to meet all three criteria in this age group. The highest antibody titres were observed in response to the 7.5 μg vaccine containing a full dose of MF59 adjuvant. All subjects rapidly generated seroprotective antibody titres in response to booster vaccination.

Conclusion

This study identified one 3.75 μg vaccine dose containing half the standard dose of MF59 adjuvant as optimal for adults, two doses were optimal for elderly subjects. The antigen-sparing properties of MF59, and rapid, modern, cell-culture production techniques represent significant steps towards meeting the global demand for influenza vaccine.     

Humoral responses to independent vaccinations are correlated in healthy boosted adults

Background

Roughly half of U.S. adults do not receive recommended booster vaccinations, but protective antibody levels are rarely measured in adults. Demographic factors, vaccination history, and responses to other vaccinations could help identify at-risk individuals. We sought to characterize rates of seroconversion and determine associations of humoral responses to multiple vaccinations in healthy adults.

Methods

Humoral responses toward measles, mumps, tetanus toxoid, pertussis, hepatitis B surface antigen, and anthrax protective antigen were measured by ELISA in post-immunization samples from 1465 healthy U.S. military members. We examined the effects of demographic and clinical factors on immunization responses, as well as assessed correlations between vaccination responses.

Results

Subsets of boosted adults did not have seroprotective levels of antibodies toward measles (10.4%), mumps (9.4%), pertussis (4.7%), hepatitis B (8.6%) or protective antigen (14.4%) detected. Half-lives of antibody responses were generally long (>30 years). Measles and mumps antibody levels were correlated (r = 0.31, p < 0.001), but not associated with select demographic features or vaccination history. Measles and mumps antibody levels also correlated with tetanus antibody response (r = 0.11, p < 0.001).

Conclusions

Vaccination responses are predominantly robust and vaccine specific. However, a small but significant portion of the vaccinated adult population may not have quantitative seroprotective antibody to common vaccine-preventable infections.     

A cell culture-derived whole-virus H5N1 vaccine induces long-lasting cross-clade protective immunity in mice which is augmented by a homologous or heterologous booster vaccination

Background

Preparation for an H5N1 influenza pandemic in humans could include priming the population in the pre-pandemic period with a vaccine produced from an existing H5N1 vaccine strain, with the possibility of boosting with a pandemic virus vaccine when it becomes available. We investigated the longevity of the immune response after one or two priming immunizations with a whole-virus H5N1 vaccine and the extent to which this can be boosted by later immunization with either a homologous or heterologous vaccine.

Methods

Mice received one or two priming immunizations with a Vero cell culture-derived, whole-virus clade 1 H5N1 vaccine formulated to contain either 750 ng or 30 ng hemagglutinin. Six months after the first priming immunization, mice received either a booster immunization with the same clade 1 vaccine or a heterologous clade 2.1 vaccine, or buffer. Humoral and cellular immune responses were evaluated before and at regular intervals after immunizations. Three weeks after booster immunization, mice were challenged with a lethal dose of wild-type H5N1 virus from clades 1, 2.1 or 2.2 and survival was monitored for 14 days.

Results

One or two priming immunizations with the 750 ng or 30 ng HA formulations, respectively, induced H5N1-neutralizing antibody titers which were maintained for ≥6 months and provided long-term cross-clade protection against wild-type virus challenge. Both humoral and cellular immune responses were substantially increased by a booster immunization after 6 months. The broadest protective immunity was provided by an immunization regimen consisting of one or two priming immunizations with a clade 1 vaccine and a boosting immunization with a clade 2.1 vaccine.

Conclusions

These data support the concept that pre-pandemic vaccination can provide robust and long-lasting H5N1 immunity which could be effectively boosted by immunization either with another pre-pandemic vaccine or with the pandemic strain vaccine.     

Anti-diphtheria immunity in Nigerian mothers and their newborns

Background

Immunity to diphtheria has been noted to wane with age such that previous studies have shown that a significant proportion of females with characteristics comparable to those of Nigerian women of reproductive age have inadequate levels of immunity to diphtheria. Thus, it is envisaged that Nigerian newborns may inherit inadequate levels of immunity to diphtheria from their mothers.

Methods

Cord blood and peripheral maternal blood samples were collected from 231 mother–infant pairs at delivery. Anti-diphtheria antibody titres were assayed using Enzyme-linked immunosorbent assay (ELISA) technique. Recruited babies were those born at term with normal birth weight.

Results

As much as 29.9% of both mothers and their babies had no protection (antibody titre < 0.01 IU/ml) from diphtheria. Ninety (39.0% CI 33%,45%) mothers and 107 (46.3% CI 40%,52%) babies were inadequately protected (antibody titre < 0.1 IU/ml) from diphtheria. The difference in the geometric mean antibody titres of mothers and babies was statistically significant (p < 0.0001). There was a strong positive linear correlation between maternal and newborn antibody titres (“r” = 0.983, p < 0.0001), such that, as mothers antibody titres increased those of their babies also increased.

Conclusion

Significant proportions of Nigerian mothers and newborns are at risk of developing diphtheria. Vaccination of parturient women with booster doses of diphtheria toxoid vaccine is recommended.     

Serotype-specific avidity is achieved following a single dose of the 7-valent pneumococcal conjugate vaccine, and is enhanced by 23-valent pneumococcal polysaccharide booster at 12 months

Aim

To evaluate whether the avidity of serotype-specific IgG to pneumococcal serotypes is enhanced by an increased number of doses of the 7-valent pneumococcal conjugate vaccine (PCV) in infancy or by a 12 month 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster, and/or subsequent re-exposure to a small dose of pneumococcal polysaccharide antigens (mPPS) at 17 months.

Methods

Fijian infants aged 6 weeks were recruited, stratified by ethnicity and randomized to 8 groups to receive 0, 1, 2, or 3 doses of PCV, with or without 23vPPS at 12 months. All children received mPPS at 17 months of age. Avidity of serotype-specific IgG for PCV serotypes in the first 12 months and for all 23vPPS serotypes thereafter was assessed by EIA after sodium thiocyanate elution.

Results

At one month post primary series, the 2 and 3 PCV dose groups demonstrated similar avidity, with the single dose group tending to have lower avidity. However, by age 9 months, the single dose group had similar avidity to the 2 and 3 PCV groups for most serotypes. The 23vPPS booster enhanced affinity maturation for most serotypes and this was most marked in those groups that received a single PCV dose. There was little further increase following the mPPS.

Conclusions

By 9 months of age, similar avidity can be induced following one, 2 or 3 doses of PCV. A 23vPPS booster at 12 months enhanced affinity maturation with an increase in antibody avidity for most serotypes. Subsequent re-challenge with mPPS at 17 months did not further enhance the avidity of serotype-specific response in the 12 month 23vPPS groups.     

Cell culture (Vero cell) derived whole-virus non-adjuvanted H5N1 influenza vaccine induces long-lasting cross-reactive memory immune response: Homologous or heterologous booster response following two dose or single dose priming

Background

Influenza pandemic preparedness involves priming of the population with pre-pandemic vaccines. Such vaccines should be well tolerated and induce a long-lasting immunological memory that can effectively be boosted with a single dose of pandemic vaccine once available. The presented studies assessed different prime-boost regimens with a Vero cell-derived whole virus non-adjuvanted H5N1 vaccine.

Methods

In one study, 281 healthy adult (18–59 years) and 280 elderly (≥60 years) subjects received two vaccinations, 21 days apart, with Vero cell-derived whole virus non-adjuvanted H5N1 vaccine (7.5 μg HA antigen A/Vietnam/1203/2004) followed by a 6, 12–15, or 24 month booster (7.5 or 3.75 μg A/Indonesia/05/2005 or A/Vietnam/1203/2004). In the other study, 230 healthy adults (18–59 years) received single dose priming (7.5 μg A/Vietnam/1203/2004) followed by a 12 month booster (7.5 or 3.75 μg A/Indonesia/05/2005). Antibody responses were assessed by microneutralization (MN) and single radial hemolysis (SRH) assay. Vaccine safety was assessed throughout.

Results

Two dose priming was equally immunogenic in adults and the elderly: >72% of subjects in each population achieved MN titers ≥1:20 after the second vaccination. Booster vaccinations at 6, 12–15, and 24 months induced substantial antibody increases to both strains: after a 7.5 μg A/Indonesia/05/2005 booster, 93–95% of adults and 72–84% of the elderly achieved MN titers ≥ 1:20 against this strain. Homologous and heterologous booster responses were higher in the 7.5 μg dose group than in the 3.75 μg dose group. Booster responses following single dose priming were similar; a 7.5 μg booster dose induced homologous MN titers ≥1:20 in 93% of subjects.

Conclusions

A Vero cell derived whole virus non-adjuvanted H5N1 influenza vaccine is well tolerated and induces long-lasting cross-clade immunological memory that can be effectively boosted 1–2 years after two dose or single dose priming, supporting its suitability for pre-pandemic vaccination.     

Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses

Background

The impact of anti-vector immunity on the elicitation of insert-specific immune responses is important to understand in vaccine development. HVTN 055 was a 150 person phase I randomized, controlled HIV vaccine trial of recombinant modified vaccinia Ankara (rMVA) and fowlpox (rFPV) with matched HIV-1 inserts which demonstrated increased CD8+ T-cell immune responses in the heterologous vaccine group. The controls used in this study were the empty vectors (MVA and FPV).

Methods

Anti-MVA and anti-vaccinia neutralizing antibodies (NAbs) were measured and compared with cellular and humoral HIV-1-specific immune responses.

Results

Elicitation of anti-vector responses increased with increasing dose of MVA and up to 2 administrations. Further inoculations of MVA (up to 5) did not increase the magnitude of the anti-MVA response but did delay the anti-vector NAb titre decay. There was no evidence that the insert impaired the anti-vector response, nor that anti-vector immunity attenuated the insert-specific responses.

Conclusion

Two doses of MVA may be ideal for the elicitation of orthopoxvirus immune responses with further doses maintaining increased titres against the vector. We found no evidence that eliciting HIV insert- or MVA vector-specific immune responses interfered with elicitation of immune responses to the other.     

Effect of needle length for response to hepatitis B vaccine in macrosomic neonates: a prospective randomized study

Objectives

The objective of this study was to determine whether use of a longer (1 in.) rather than a standard (5/8 in.) needle used for macrosomic neonates (birthweight over 4000 g) may affect antibody titers after immunization against hepatitis B virus (HBV).

Methods

Fifty nine healthy infants were vaccinated at birth, 1, and 6 months of age with hepatitis B vaccine, with follow up to 7 months of age. Infants were randomized into two groups according to needle length of first vaccine at birth. First group vaccinated with standart needle length and other group received vaccine by longer needle length.

Results

Macrosomic infants who were immunized with a longer needle achieved significantly higher antibody titers to hepatitis B surface antigen than standart needle length (median, 3890.2 vs 1311.7 mIU/mL, respectively; p = 0.001).

Conclusions

Macrosomic neonates benefit from longer needle length with higher levels of antibody titers after HBV vaccination.