Delta inulin polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against lethal challenge in ferrets

Background

The reduced immunogenicity of the H5 hemagglutinin (HA), compared to seasonal HA serotypes, has stimulated searches for effective adjuvants to improve H5 vaccine efficacy. This study examined the immunogenicity and protective efficacy in ferrets immunized with a split-virion H5N1 vaccine combined with Advax™, a novel delta inulin-based polysaccharide adjuvant technology that has previously demonstrated ability to augment humoral and cellular immunity to co-administered antigens.

Methods

Ferrets were vaccinated twice 21 days apart with 7.5 μg or 22.5 μg of a split-virion preparation of A/Vietnam/1203/2004 with or without adjuvant. An additional group received just one immunization with 22.5 μg HA plus adjuvant. Serum antibodies were measured by hemagglutination inhibition and microneutralization assays. Vaccinated animals were challenged intranasally 21 days after the last immunization with 10⁶ EID₅₀ of the homologous strain. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load.

Results

No serum neutralization antibody was detected after two immunizations with unadjuvanted vaccine. Two immunizations with high or low dose adjuvanted vaccine stimulated high neutralizing antibody titers. Survival was 100% in all groups receiving adjuvanted-vaccine including the single dose group, compared to 67% survival with unadjuvanted vaccine, and 0% survival in saline or adjuvant-alone controls. Minimal morbidity was seen in all animals receiving adjuvanted vaccine, and was limited to rhinorrhea and mild thrombocytopenia, without fever, weight loss, or reduced activity. H5N1 virus was cleared from the nasal wash by day 4 post-challenge only in animals receiving adjuvanted vaccine which also prevented viral invasion of the brain in most animals.

Conclusions

In this initial study, Advax™ adjuvant formulations improved the protective efficacy of a split-virion H5N1vaccine as measured by significantly enhanced immunogenicity, survival, and reduced morbidity.     

Serum IgG titres,but not avidity,correlates with neutralizing antibody response after H5N1 vaccination

Background

Influenza H5N1 virus constitutes a pandemic threat and development of effective H5N1 vaccines is a global priority. Anti-influenza antibodies directed towards the haemagglutinin (HA) define a correlate of protection. Both antibody concentration and avidity may be important for virus neutralization and resolving influenza disease.

Methods

We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with the immunostimulating complex Matrix M™. Sixty adults were intramuscularly immunized with two vaccine doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M™. Serum H5 HA1-specific antibodies and virus neutralization were determined at days 0, 21, 42, 180 and 360 and long-term memory B cells at day 360 post-vaccination. The binding of the HA specific antibodies was measured by avidity NaSCN-elution ELISA and surface plasmon resonance (SPR).

Results

The H5 HA1-specific IgG response peaked after the second dose (day 42), was dominated by IgG1 and IgG3 and was highest in the adjuvanted vaccine groups. IgG titres correlated significantly with virus neutralization at all time points (Spearman r ≥ 0.66, p < 0.0001). By elution ELISA, serum antibody avidity was highest at days 180 and 360 post vaccination and did not correlate with virus neutralization. Long-lasting H5 HA1-specific memory B cells produced high IgG antibody avidity similar to serum IgG.

Conclusions

Maturation of serum antibody avidity continued up to day 360 after influenza H5N1 vaccination. Virus neutralization correlated with serum H5 HA1-specific IgG antibody concentrations and not antibody avidity.     

Text message reminders to promote human papillomavirus vaccination

Objective

To implement and evaluate text message reminders for the second (HPV2) and third (HPV3) vaccine doses.

Design

Site-based intervention.

Setting

Nine pediatric sites (5 academic and 4 private) located in New York City.

Participants

Parents of adolescents 9-20 years who received HPV1 or HPV2 during the intervention period, January-June 2009.

Intervention

Parents who enrolled received up to three weekly text message reminders that their daughter was due for her next vaccine dose.

Outcome measure

On-time receipt of the next vaccine dose, within one month of its due date.

Results

During the intervention period, of 765 eligible HPV vaccine events, 434 enrollment instructions were distributed to parents (56.7% of doses). Parents of 124 adolescent girls (28.6% of those handed instructions) activated text message reminders. Comparing children of parents who enrolled versus those who did not, on-time receipt of next HPV vaccine dose occurred among 51.6% (95% CI 42.8-60.4%) versus 35.0% (95% CI 29.6-40.2%) of adolescents (p = .001). Similarly, among a historical cohort of adolescents, receiving HPV1 or HPV2 in the six months prior to the intervention period, on-time receipt of next vaccine dose was noted for 38.1% (95% CI 35.2-41.0%) (p = .003). Increases in receipt of next vaccine dose among intervention subjects were sustained at 4 months following the vaccine due date. Using a logistic regression model, after controlling for insurance and site of care, intervention subjects were significantly more likely than either control population to receive their next HPV vaccine dose on-time.

Conclusion

Among those choosing to enroll, text message reminders were an effective intervention to increase on-time receipt of HPV2 or HPV3.     

The immunogenicity and safety of pneumococcal conjugate vaccine in human immunodeficiency virus-infected Thai children

Background

HIV-infected children have high risk of invasive pneumococcal disease (IPD) despite receiving highly active antiretroviral therapy (HAART). This study aimed to determine the immunogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV-7) in Thai HIV-infected children compared to HIV-exposed uninfected children.

Methods

A prospective study was conducted among children 2 months to 9 years. The number of PCV-7 doses depended upon age and HIV status; 2-6 months of age: 3 doses; 7-23 months of age: 2 doses; HIV-infected child ≥24 months: 2 doses and HIV-exposed child ≥24 months: 1 dose. Serotype-specific pneumococcal IgG antibody concentrations were measured at baseline and 28 days after complete vaccination. The primary end point was the proportion of children who achieved serotype-specific IgG antibody concentration at a cut off level ≥0.35 μg/mL. Secondary end points were a 4-fold increase in serotype-specific IgG antibody, rates of adverse events and predictors for seroconversion among HIV-infected children.

Results

Fifty-nine HIV-infected and 30 HIV-exposed children were enrolled. The median (IQR) age was 97 (67-111) and 61 months (51-73), respectively (p < 0.001). Among HIV-infected children, current and nadir CD4 counts were 1079 cell/mm³ and 461 cell/mm³, respectively. The proportion of children who achieved pneumococcal IgG ≥0.35 μg/mL was in the range of 85-98% in HIV-infected and 83-100% in HIV-exposed children depending on serotype. The lowest response was to serotype 6B in both groups. The 4-fold increase in serotype-specific IgG concentrations was similar between HIV-infected and HIV-exposed groups, except for serotype 9V (p = 0.027). HIV-infected children who had a history of AIDS had a lower antibody response to serotype 23F (p = 0.025). Seven (12%) HIV-infected children had a grade 3 local reaction.

Conclusion

PCV-7 is highly immunogenic and safe among HIV-infected children treated with HAART. The use of the pneumococcal conjugate vaccine among HIV-infected children is encouraged in order to prevent IPD.     

Surface antibody and cytokine response to recombinant Chinese hamster ovary cell (CHO) hepatitis B vaccine

Objective

To compare the immune responses of the 10 μg and 20 μg doses of CHO hepatitis B vaccine on adults.

Methods

Adults aged 18-45 years who gave a history of never having received hepatitis B vaccine and lacked serologic evidence of infection to hepatitis B virus (HBV) infection or previous vaccination were enrolled into the study. A total of 642 eligible participants were randomized to receive 3 doses of either the 10 μg or the 20 μg formulation of CHO hepatitis B vaccine in a 0-1-6 month schedule. Each study subject had a serologic specimen collected one month following the third vaccine dose that was tested for markers of HBV infection and anti-HBs by Abbott I2000. Persons who tested negative for anti-HBs negative persons were tested for HBV DNA. Logistic regression was used to identify factors associated with antibody response. Among the participants, 153 subjects had their lymphocytes cultivated and tested for cytokine production. Enzyme-linked immunospot (ELISPOT) was used to test spot numbers of IL-4, IFN-γ which produced by lymphocyte.

Results

The anti-HBs seroconversion rate was 88.8% (95% CI: 85.4-92.2%) and 95.3% (95% CI: 93.0-97.6%), respectively in 10 μg and 20 μg group. Geometric mean titers (GMT) were 173.42 mIU/ml and 585.51 mIU/ml, respectively in 10 μg and 20 μg groups. Multivariate analysis demonstrated that diabetes, spouse is hepatitis B virus infector, older age and receipt of the 10 μg dose were all negatively associated with antibody response (P < .05). Cellular immunity results showed: IL-4 immunity spot numbers in 20 μg group was higher than 10 μg group. With anti-HBs increased, the IL-4 immunity spot numbers increased significantly which had significant positive correlation (Spearman coefficient = 0.538, P < 0.0001). IFN-γ spot numbers had no statistical significant between the two groups.

Conclusion

The humoral immunity and cytokines response among the group that received the 20 μg CHO hepatitis B vaccine dose was superior compared to the group that received the 10 μg dose. The 20 μg dose of CHO hepatitis B vaccine should be prioritized for adult vaccination programs in China.     

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.     

Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults

Background

The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults.

Methods

Sixty subjects 18-49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration.

Results

Doses of 0.03-1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses (p > 0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 μg), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release.

Conclusions

VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 μg doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation.     

Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Background

Shigella flexneri 2a lipopolysaccharide 50 is a nasally delivered subunit vaccine consisting of a macromolecular complex composed of LPS, IpaB, IpaC and IpaD. The current study examined vaccine safety and immunogenicity across a dose range and the clinical performance of a new intranasal delivery device.

Methods

Volunteers (N = 36) were randomized to receive vaccine via the Dolphin™ (Valois of America, Congers, New York) intranasal spray device at one of three doses (240, 480, and 690 μg) on days 0, 14, and 28. Another group (N = 8) received the 240 μg dose via pipette. Vaccine safety was actively monitored and antigen-specific humoral and mucosal immune responses were determined.

Results

There were no serious adverse events and the majority of adverse events (98%) were mild. Antibody secreting cells (ASC), plasma, and mucosal immune responses to Shigella antigens were detected at all three dose levels with the 690 μg dose inducing the highest magnitude and frequency of responses. Vaccination with comparable doses of Invaplex 50 via the Dolphin™ resulted in higher plasma and ASC immune responses as compared to pipette delivery.

Conclusion

In this trial the S. flexneri 2a Invaplex 50 vaccine was safe, well-tolerated and induced robust levels of antigen-specific intestinal IgA and ASC responses. The spray device performed well and offered an advantage over pipette intranasal delivery.     

Safety and immunogenicity of pneumococcal protein vaccine candidates: Monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA–pneumococcal histidine triad protein D vaccine

Background

Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae.

Objective

To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations.

Methods

This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)–adjuvanted PcpA (25 μg) or PhtD–PcpA (10 μg each), participants in the main study received AH–adjuvanted PcpA (25 μg), AH–adjuvanted PhtD–PcpA (10, 25, or 50 μg each), unadjuvanted PhtD–PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA).

Results

Six adults 18–50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases.

Conclusions

Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).     

A Phase I,randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine

Background

Large-scale outbreaks of enterovirus 71 (EV71) infections have occurred in Asia-Pacific regions. Severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against EV71.

Methods

In this randomized Phase I study, we evaluated the safety and immunogenicity of an inactivated alum-adjuvanted EV71 whole-virus vaccine produced on Vero cell cultures. Sixty healthy volunteers aged 20–60 years received two doses of vaccine, administered 21 days apart. Each dose contained either 5 μg of EV71 antigen with 150 μg of adjuvant (Group A05) or 10 μg of EV71 antigen with 300 μg of adjuvant (Group B10). Serologic analysis was performed at baseline, day 21, and day 42.

Results

There were no serious adverse events. Mild injection site pain and myalgia were the most common adverse events with either vaccine formulation. The immunogenicity data showed that 90% of vaccine recipients have a 4-fold or greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rates on day 21 and day 42 were 86.7% and 93.1% respectively, in Group A05, and 92.9% and 96.3%, respectively, in Group B10. Thus, 5 μg and 10 μg of the EV71 vaccine can induce a remarkable immune response in healthy adults after only the first vaccination.

Conclusion

The 5 μg and 10 μg adjuvanted EV71 vaccines are generally safe and immunogenic in healthy adults. (ClinicalTrials.gov number, NCT01268787).     

Evaluation of hepatitis B vaccine immunogenicity among older adults during an outbreak response in assisted living facilities

Background

During the past decade, in the United States, an increasing number of hepatitis B outbreaks have been reported in assisted living facilities (ALFs) as a result of breaches in infection control practices. We evaluated the seroprotection rates conferred by hepatitis B vaccine among older adults during a response to an outbreak that occurred in multiple ALFs and assessed the influence of demographic and clinical factors on vaccine response.

Methods

Residents were screened for hepatitis B and C infection prior to vaccination and susceptible residents were vaccinated against hepatitis B with one dose of 20 μg Engerix-B™ (GSK) given at 0, 1, and 4 months. Blood samples were collected 80-90 days after the third vaccine dose to test for anti-HBs levels.

Results

Of the 48 residents who had post-vaccination blood specimens collected after the third vaccine dose, 16 (33.3%) achieved anti-HBs concentration ≥10 mIU/mL. Age was a significant determinant of seroprotection with rates decreasing from 88% among persons aged ≤60 years to 12% among persons aged ≥90 years (p = 0.001). Geometric mean concentrations were higher among non-diabetic than diabetic residents, however, the difference was not statistically significant (5.1 vs. 3.8 mIU/mL, p = 0.7).

Conclusions

These findings highlight that hepatitis B vaccination is of limited effectiveness when administered to older adults. Improvements in infection control and vaccination at earlier ages might be necessary to prevent spread of infection in ALFs.     

Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: A phase I–II randomized trial

Objective

Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children.

Methods

An open-labelled phase I trial was conducted in children aged 3–11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5–30 μg) and in children aged 12–17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5–15 μg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3–11 years received the split-virion vaccine (10 or 15 μg) and 280 children aged 12–17 years received the split-virion vaccine (10–30 μg) or the whole-virion vaccine (5 μg). Serum samples were collected for hemagglutination-inhibition (HI) assays.

Findings

5–15 μg adjuvated split-virion vaccines were well tolerated in children aged 3–11 years and 5–30 μg adjuvated split-virion vaccines and 5 μg adjuvated whole-virion vaccine were well tolerated in children aged 12–17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3–11 years children, the 10 and 15 μg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer ≥1:40) rates. In 12–17 years children, the 30 μg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 μg whole-virion vaccine induced higher response than the 10 μg split-virion vaccine did.

Interpretation

The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 μg dose induced immune response complying with European Union licensure criteria. [ClinicalTrials.gov identifiers: NCT00900588 and NCT00900991].     

Immunogenicity and safety of a Haemophilus influenzae B (Hib)-hepatitis B vaccine with a modified process hepatitis B component administered with concomitant pneumococcal conjugate vaccine to infants

Background

A hepatitis B vaccine was manufactured with a modified process (mpHBV) that incorporated double the usual amount of phosphate. Following a study in young adults, the mpHBV was evaluated in infants in a combination hepatitis B and Haemophilus influenzae B vaccine (mpHBV-Hib).

Methods

The mpHBV-Hib was compared with the licensed bivalent HBV-Hib vaccine Comvax™ for immunogenicity and safety. Both vaccines contained 5 μg/0.5 mL of hepatitis B surface antigen (HBsAg) and 7.5 μg/0.5 mL of PRP-OMPC (polyribosylribitol phosphate outer membrane protein complex). A total of 543 infants were randomized 1:1 to receive either vaccine at 2, 4 and 12 months of age. A pneumococcal conjugate vaccine (PCV) was given concomitantly. Immunogenicity was assessed at 1-month post-dose 3.

Results

Seroprotection rates [% subjects with anti-hepatitis B surface antigen antibody titers (anti-HBs) ≥10 mIU/mL)] were 100% and 99% for mpHBV-Hib and the licensed control (Comvax™), respectively. Anti-HBs geometric mean titers (GMTs) were 4204 (95% CI, 3411-5182) and 1683 (95% CI, 1350-2099) mIU/mL, respectively. Anti-PRP seroprotection rates (SPR) at ≥0.15 μg/mL and at ≥1.0 μg/mL were 97% and 94%, respectively, for mpHBV-Hib and 96% and 92%, respectively, for the control. Anti-PRP GMTs were 7.1 μg/mL for mpHBV-Hib and 8.0 μg/mL for the control. Reactogenicity of the two vaccines was similar.

Conclusions

The mpHBV in combination with Hib and with co-administered PCV was highly immunogenic. The safety profile of mpHBV-Hib was comparable to the licensed control. Both the control and mpHBV-Hib met acceptability criteria for seroprotection rates to hepatitis B, with higher anti-HBs GMTs noted for mpHBV-Hib.     

A phase I randomized, double-blind, controlled trial of 2009 influenza A (H1N1) inactivated monovalent vaccines with different adjuvant systems

Methods

We conducted a phase I, multicenter, randomized, double-blind, placebo-controlled, multi-arm (10) parallel study involving healthy adults to evaluate the safety and immunogenicity of influenza A (H1N1) 2009 non-adjuvanted and adjuvanted candidate vaccines. Subjects received two intramuscular injections of one of the candidate vaccines administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay before and 21 days after each vaccination. The three co-primary immunogenicity end points were the proportion of seroprotection >70%, seroconversion >40%, and the factor increase in the geometric mean titer >2.5.

Results

A total of 266 participants were enrolled into the study. No deaths or serious adverse events were reported. The most commonly solicited local and systemic adverse events were injection-site pain and headache, respectively. Only three subjects (1.1%) reported severe injection-site pain. Four 2009 influenza A (H1N1) inactivated monovalent candidate vaccines that met the three requirements to evaluate influenza protection, after a single dose, were identified: 15 μg of hemagglutinin antigen without adjuvant; 7.5 μg of hemagglutinin antigen with aluminum hydroxide, MPL and squalene; 3.75 μg of hemagglutinin antigen with aluminum hydroxide and MPL; and 3.75 μg of hemagglutinin antigen with aluminum hydroxide and squalene.

Conclusions

Adjuvant systems can be safely used in influenza vaccines, including the adjuvant monophosphoryl lipid A (MPL) derived from Bordetella pertussis with squalene and aluminum hydroxide, MPL with aluminum hydroxide, and squalene and aluminum hydroxide.     

Immunogenicity of hepatitis B vaccine among hemodialysis patients: effect of revaccination of non-responders and duration of protection

Background

Hepatitis B vaccination is recommended for patients on hemodialysis, however, seroprotection after a primary vaccine series is suboptimum. Limited data are available on the effect of revaccination of non-responders and on persistence of immunity in this population.

Methods

Hepatitis B vaccine (40 μg/dose) was given to 77 susceptible patients on hemodialysis (0, 1, and 6 month schedule). Levels of hepatitis B surface antibody (anti-HBs) were tested ≥28 days after the third dose was administered, and non-responders revaccinated with an additional 3-dose series. Vaccine responders (anti-HBs ≥10 mIU/mL) were re-tested every 6 months and booster doses given as needed. Kaplan-Meier survival curve was used to estimate the probability of maintaining protective antibody level. Cox-proportional hazards models were used to assess the association between time to loss of protective antibody levels and certain explanatory variables.

Results

Overall primary vaccine-induced response was 79.2% (95% CI 68.2%, 87.3%), including 49/77 (63.6%; 95% CI 51.8%, 74.7%) patients who received the initial primary hepatitis B vaccine series and 12/21 (57.1%; 95% CI 34.4%, 77.4%) non-responders who were revaccinated with an additional series. Among weak responders (anti-HBs level 10.0-99.9 mIU/mL), protective antibody levels persisted in 44% for 12 months post-vaccination; whereas among strong responders (anti-HBs level ≥100 mIU/mL), protective antibody levels persisted in 92% for 12 months, and 68% for 24 months post-vaccination. A weak post-vaccination response increased the risk of losing protective antibody levels (adjusted hazard ratio, 9.7; 95% confidence interval, 3.5-28.5; p < 0.0001).

Conclusion

Revaccinating patients undergoing hemodialysis who do not respond to a primary vaccine series substantially increases the pool of protected patients. The threshold for defining hepatitis B vaccine-induced immunity should be revisited in this patient population to maximize the duration of protection.     

Tolerability and antibody response in adolescents and adults revaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) 4-5 years after a previous dose

Background

Although decennial adult boosters of tetanus and diphtheria toxoids are recommended in Canada and the United States, a second dose of pertussis vaccine is not currently recommended for adults.

Methods

This open-label, postmarketing, multicenter study evaluated the tolerability and immunogenicity of a second dose of an adult formulation of tetanus, diphtheria, and pertussis vaccine (Tdap) in adolescents and adults 5 years after a first dose.

Results

A total of 545 participants from previous Tdap vaccine studies, ranging in age from 15 to 69 years, participated in this study. Of these participants, 94.2% had at least one solicited adverse event after the booster dose such as injection-site erythema (28.6%), swelling (25.6%), or pain (87.6%) or a systemic adverse event such as myalgia (61.0%), headache (53.2%), malaise (38.2%), or fever (6.5%). These adverse events were slightly more frequent than after the initial dose. Postvaccination, 100% of participants had a tetanus antibody level ≥0.10 IU/mL and 95% had a diphtheria antibody level ≥0.10 IU/mL. For pertussis, 82.1% (pertussis toxoid), 96.7% (filamentous hemagglutinin), 95.6% (pertactin), and 99.8% (fimbriae) had a postvaccination antibody threshold of ≥50 EU/mL.

Conclusion

A second dose of Tdap vaccine 5 years after the initial dose was well tolerated and immunogenic in adolescents and adults.     

Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine

Objective

We performed a Phase 1 randomized, observer-blinded, placebo-controlled trial to evaluate the safety and immunogenicity of a recombinant respiratory syncytial virus (RSV) fusion (F) protein nanoparticle vaccine.

Methods

Six formulations with (5, 15, 30 and 60 μg) and without (30 and 60 μg) aluminum phosphate (AdjuPhos) were administered intramuscularly on day 0 and 30 in a dose escalating fashion to healthy adults 18–49 years of age. Solicited and unsolicited events were collected through day 210. Immunogenicity measures taken at day 0, 30 and 60 included RSV A and B microneutralization, anti-F IgG, antigenic site II peptide and palivizumab competitive antibodies.

Results

The vaccine was well-tolerated, with no evident dose-related toxicity or attributable SAEs. At day 60 both RSV A and B microneutralization was significantly increased in vaccinees versus placebo. Across all vaccinees there was a 7- to 19-fold increase in the anti-F IgG and a 7- to 24-fold increase in the antigenic site II binding and palivizumab competitive antibodies.

Conclusions

The RSV F nanoparticle vaccine candidate was well tolerated without dose-related increases in adverse events. Measures of immunity indicate that neutralization, anti-RSV F IgG titers and palivizumab competing antibodies were induced at levels that have been associated with decreased risk of hospitalization.NCT01290419.     

Safety and immunogenicity of whole-virus,alum-adjuvanted whole-virus,virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations

Avian influenza H9N2 viruses are considered as a pandemic threat. We assessed the safety and immunogenicity of fourteen H9N2 vaccine formulations. A randomized, phase I trial was done in 353 adults, aged 18–82 years. Subjects received two doses of A/Hong Kong/1073/99 (H9N2) whole-virus, alum-adjuvanted whole-virus, virosomal, or intradermal whole-virus vaccine at four doses (1.7, 5, 15 or 45 μg haemagglutinin). Sera were obtained before and three weeks after each vaccination (days 0, 21, and 42) for haemagglutination–inhibition (HAI) and neutralization assays. All formulations were well tolerated. Pre-vaccination sera from subjects aged below or above 40 years had baseline antibody to H9N2 in 1% and 16% of samples. Compared to intramuscular whole-virus vaccine, alum-adjuvanted vaccine was more immunogenic, intradermal vaccine was comparable, and virosomal vaccine less immunogenic. Among subjects under 40 years, two doses (45, 15, and 5 μg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 41%, and 39% respectively, and neutralization seroconversions in 83%, 82%, and 78% of recipients. Among subjects over 40 years, one dose (45, 15, and 5 μg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 25% and 0% respectively, and neutralization seroconversions in 88%, 63% and 63% of recipients. Among immunologically naive subjects under 40 years, two doses of vaccine are required and alum-adjuvanted vaccines were most immunogenic. Among immunologically primed subjects over 40 years, one dose of whole-virus or alum-adjuvanted vaccine induced immune responses; the second dose provided less additional benefit. However, no vaccine formulation satisfied all European regulatory criteria for pandemic vaccines.     

A randomized, double-blind, placebo-controlled, phase 1/2a study of the safety and immunogenicity of a live, attenuated human parainfluenza virus type 3 vaccine in healthy infants

Objective

To evaluate the safety, tolerability, immunogenicity, and viral shedding profiles of a recombinant, live, attenuated human parainfluenza virus type 3 (HPIV3) vaccine, rHPIV3cp45, in healthy HPIV3-seronegative infants 6 to <12 months of age.

Methods

In this double-blind, multicenter study, subjects were randomized 2:1 to receive a 10⁵ TCID₅₀ dose of rHPIV3cp45 (n = 20) or placebo (n = 10) at enrollment and at 2 and 4 months after the first dose. Blood for evaluation of antibody to HPIV3 was collected at baseline and approximately 1 month after each dose. Solicited adverse events (SEs) and unsolicited adverse events (AEs) were collected on days 0-28 after each dose. Nasal wash samples for vaccine virus shedding were collected 3 times after each dose (7-10, 12-18, and 28-34 days post dose) and at unscheduled illness visits. Subjects were followed for 180 days after the last dose.

Results

Vaccine virus was shed by 85% of vaccine recipients after dose 1, by 1 subject after dose 2, and was not shed by any subject after dose 3. The highest titer of shed virus was detected on day 7 after dose 1. The attenuation phenotype and the genotype of the vaccine virus were stable in shed virus. Seroresponse (≥4-fold rise in HPIV3 antibody from baseline) occurred in 61% of subjects after dose 1 and in 77% after dose 3. Either seroresponse or shedding occurred in 95% of vaccine subjects. Adverse events were similar in vaccine and placebo recipients.

Conclusion

The safety, shedding, and immunogenicity profiles of rHPIV3cp45 in HPIV3-seronegative infants 6 to <12 months of age support further development of this vaccine.ClinicalTrials.gov Identifier: NCT00508651.     

Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media

Background

The goal of this study was to evaluate whether a live attenuated poliovirus vaccine (OPV) has clinically relevant interfering effect with non-polio infections causing otitis media in young children.

Methods

Open trial in which the intervention group (64 children) received OPV at the age of 2, 3, 6 and 12 months. The control group (250 children) received IPV (inactivated polio vaccine) at the age of 6 and 12 months. Clinical symptoms were recorded by a questionnaire at the age of 3, 6, 12, 18 and 24 months.

Results

Otitis media episodes were less frequent in the OPV than in the control group. A significant difference was seen at the age of 6-18 months (IRR = 0.76 [95% CI 0.59-0.94], P = 0.011) and was particularly clear among children, who attended daycare (IRR 0.37 [95% CI 0.19-0.71], P = 0.003).

Conclusions

OPV provides some protection against otitis media. This effect may be mediated by viral interference with non-polio viruses.