The role of nasal IgA in children vaccinated with live attenuated influenza vaccine.

BACKGROUND: Immunoglobulin A (IgA) is the predominant antibody produced in response to mucosal infections. The role of IgA in providing protection against influenza in children vaccinated with live attenuated influenza vaccine (LAIV) has not been well described. METHODS: Nasal IgA responses were assessed using data from 3 prospective, 2-year, randomized studies comparing LAIV with placebo in children 6-36 months of age. In each study, samples were collected in a subset of patients; a new cohort was enrolled each year. Ratios of strain-specific nasal IgA to total nasal IgA were calculated and prevaccination to postvaccination geometric mean fold-rises (GMFRs) were evaluated. Mean postvaccination IgA ratios were compared for subjects with and without confirmed influenza illness by study and in pooled analyses. RESULTS: Across studies, a higher percentage of children receiving LAIV had a ≥ 2-fold increase in strain-specific IgA ratio compared with placebo recipients. GMFRs after LAIV in years 1 and 2 ranged from 1.2 to 6.2, compared with 0.5-2.2 among placebo recipients. Similar responses were observed in subjects who were baseline seronegative and seropositive based on serum hemagglutination inhibition antibody titers. In years 1 and 2, the mean postvaccination strain-specific to total IgA ratio was 3.1-fold (P<0.01) and 2.0-fold (P<0.03) higher among LAIV recipients with no evidence of culture-confirmed influenza illness compared with LAIV recipients who developed culture-confirmed influenza illness; a similar and consistent trend was observed for each individual study and type/subtype. CONCLUSIONS: The current analysis demonstrates that nasal IgA contributes to the efficacy of LAIV and can provide evidence of vaccine-induced immunity. However, the inherent heterogeneity in nasal antibody levels and variability in nasal specimen collection hinders the precise evaluation of mucosal antibody responses. Other studies have demonstrated that LAIV-induced immunity is also partially explained by T-cell immunity, serum antibody responses, and innate immunity, consistent with the multi-faceted nature of immunity induced by wild-type influenza infection and other live virus vaccines.

Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials.

BACKGROUND: The safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV) were evaluated in children and adults. METHODS/PRINCIPAL FINDINGS: Two randomized, double-blind, placebo-controlled studies were completed in children (2-17 y) and adults (18-49 y). Subjects were assigned 4:1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1-8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65) and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60) were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5%) pediatric vaccine recipients and 1 (1.5%) placebo recipient (rate difference, 0%; 95% CI: -6.4%, 3.1%). No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo) were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: -9.6%, 13.8%) and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%). Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: -5.6%, 12.6%) and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: -0.8%, 16.3%) after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo) occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred. CONCLUSIONS/SIGNIFICANCE: In subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT00946101, NCT00945893.

Vacc-4x, a therapeutic vaccine comprised of four engineered peptides for the potential treatment of HIV infection.

Vacc-4x is being developed by Bionor Immuno AS as a therapeutic vaccine to be used in conjunction with antiretroviral therapies by individuals infected with HIV. The vaccine is comprised of four synthetic peptides describing sequences from within the highly conserved HIV core protein p24, which are thought to induce T-cell-mediated responses. Vacc-4x was assessed in 51 patients infected with HIV in one phase I and one phase II clinical trial and was demonstrated to be safe and generally well tolerated with no significant adverse events. Promisingly, the vaccine was reported to induce cell-mediated immunity, with a third of vaccinees eligible for follow-up remaining off antiretroviral therapy and being essentially symptom-free 4 years after treatment. Nonetheless, without the inclusion of a placebo group, the data will be looked upon with a degree of skepticism in the scientific community. A phase IIb, placebo-controlled clinical trial to address this issue is currently ongoing, with data expected to become available by the end of 2010. If Vacc-4x vaccinees demonstrate significantly better responses than the placebo group in this trial, the prospects for Vacc-4x could be highly promising.

GSK's novel split-virus adjuvanted vaccines for the prevention of the H5N1 strain of avian influenza infection.

Although influenza pandemics occur infrequently, they are unpredictable. Given that humans had not been previously exposed to the novel H5N1 strain, few (if any) individuals have any degree of immunity to the strain. GlaxoSmithKline plc (GSK) has developed two inactivated split H5N1 vaccines adjuvanted with GSK's proprietary oil-in-water emulsion AS03: GSK-1562902A (produced in Dresden, Germany) and GSK-1557484A (produced in Québec, Canada). The vaccines principally use an A/Vietnam strain virus; following the vaccination of influenza-naïve ferrets, potent neutralizing titers against the homologous A/Vietnam strain virus and against a heterologous A/Indonesia strain virus were elicited. In phase I, II and III clinical trials, two administrations of low doses (3.8 microg) of the vaccines induced protective immunity in more than 90% of vaccinees. The vaccines were generally well tolerated; the most frequently reported local adverse event was pain at the injection site. The vaccines, which can be administered in the pre-pandemic and pandemic setting, were approved in Europe in May 2008 as Prepandrix and Pandemrix, respectively. Phase II/III trials were also ongoing at the time of publication for both GSK-1562902A and GSK-1557484A. With the enormous demand for an effective vaccine in the event of an H5N1 pandemic, GSK's inactivated split H5N1 virus vaccine likely will be a highly valued product.

IC-51, an injectable vaccine for the prevention of Japanese encephalitis virus infection.

The mosquito-borne Japanese encephalitis (JE) virus is the major etiological agent of viral encephalitis in children living in South-East Asia, causing comas, seizures and Parkinson's disease-like movement disorders. Travelers and military personnel visiting the region are also highly susceptible to the disease. As the population in South-East Asia increases, more land is irrigated to produce rice paddies (the ideal breeding habitat for mosquitoes), and pig breeding (a zoonotic host for mosquitoes) becomes more widespread. Given the exponential growth in tourism to the region and the globalization of business and commerce, an enhanced requirement for mass vaccination exists. In the West, the current licensed vaccine against JE, JE-VAX, has been highly effective; however, the use of mouse brain-derived virus has been linked to cases of acute disseminated encephalomyelitis. Intercell AG, under license from VaccGen International LLC, is developing IC-51, a formalin-inactivated vaccine derived from cell culture-based attenuated virus that has been adapted to grow in Vero cells (African green monkey kidney cells). In extensive clinical trials performed to date, IC-51 was safe, with mild to moderate adverse events reported. In terms of immunogenicity, IC-51 was highly effective, demonstrating rapid seroconversion rates and long-term maintenance of geometric mean titers that exceeded the protective titer. The results suggests that IC-51 is fully compliant with the stringent regulatory requirements set by the WHO, has an acceptable safety profile and is non-inferior to JE-VAX.

IMVAMUNE, an attenuated modified vaccinia Ankara virus vaccine for smallpox infection.

Bavarian Nordic is developing IMVAMUNE, which is based on a live attenuated modified vaccinia Ankara virus, for the potential prevention of smallpox infection, particularly in those patients contraindicated to traditional smallpox vaccines, such as the immunocompromised and those with eczema or dermatitis. In phase I and II clinical trials, IMVAMUNE was highly immunogenic and safe with no unexpected side effects or serious adverse effects reported in either healthy volunteers, those immunocompromised by HIV infection or in volunteers with atopic dermatitis. Additional phase II trials were ongoing in these groups at the time of publication and phase III trials were planned for 2009.

Intranasal Protollin-formulated recombinant SARS S-protein elicits respiratory and serum neutralizing antibodies and protection in mice.

The feasibility of developing a prophylactic vaccine against SARS was assessed by comparing the immune responses elicited by immunizing mice with a recombinant SARS spike glycoprotein (S-protein) formulated with different adjuvants, given by different routes. In both young and aged mice, an intranasal Protollin-formulated S-protein vaccine elicited high levels of antigen-specific IgG in serum, comparable to those elicited by an intramuscular Alum-adsorbed S-protein vaccine. Serum antibodies were shown to be virus neutralizing. Intranasal immunization of young mice with the Protollin-formulated vaccine elicited significant levels of antigen-specific lung IgA in contrast to mice immunized with the intramuscular vaccine in which no antigen-specific lung IgA was detected. Following live virus challenge of aged mice, no virus was detected in the lungs of intranasally immunized mice, in contrast to intramuscularly immunized mice whose lung virus titers were comparable to those observed in control mice.

Intranasal proteosome-based respiratory syncytial virus (RSV) vaccines protect BALB/c mice against challenge without eosinophilia or enhanced pathology.

A safe and effective vaccine against respiratory syncytial virus (RSV) is still unavailable. Proteosome-based adjuvants are derived from the outer membrane proteins (OMP) of Neisseria species and are potent inducers of both mucosal and systemic immunity in humans and animals. Candidate RSV subunit vaccines comprising enriched RSV proteins (eRSV) formulated with proteosomes alone or with LPS (Protollin) were produced. Administered intranasally in BALB/c mice, both vaccines elicited long-lasting systemic and mucosal RSV-specific antibodies and fully protected against challenge. In vitro restimulation of lymphocytes from the Protollin-eRSV immunized mice with F (MHC-I) and G (MHC-II) peptides elicited F peptide-specific CD8(+) T cells and supernatant IFNgamma, TNFalpha, IL-2 and IL-10 while the formalin-inactivated RSV (FI-RSV) vaccine elicited predominantly IL-5. Pulmonary eosinophilia did not develop following immunization with either proteosome-based vaccine following challenge compared to mice immunized with FI-RSV. Proteosome-based eRSV vaccines can therefore protect against RSV challenge in mice without increasing the risk of pulmonary immunopathologic responses.

C57Bl/6 mice are protected from respiratory syncytial virus (RSV) challenge and IL-5 associated pulmonary eosinophilic infiltrates following intranasal immunization with Protollin-eRSV vaccine.

The protective efficacy of an intranasal (IN) Protollin-eRSV vaccine has recently been demonstrated in the RSV-susceptible BALB/c mouse model. Here, we report the safety, immunogenicity and efficacy of Protollin-eRSV vaccine in the relatively resistant C57Bl/6 mouse model. C57Bl/6 mice immunized IN with either two or three doses of Protollin-eRSV produced significant systemic and mucosal RSV-specific antibodies. Mice immunized with the Protollin vaccine displayed polarized Th1 responses with augmented IFNgamma/IL-5 ratios in RSV-restimulated lung and spleen cell preparations compared with animals that received antigen alone. The Protollin-eRSV immunized C57Bl/6 mice were fully protected against challenge without eosinophilic pulmonary pathology observed in the animals immunized with the formalin-inactivated RSV vaccine. This new model will permit us to dissect the respective roles of the TLR2 and TLR4 ligands contained in the vaccine using TLR knock-out animals established on the C57Bl/6 background.

Intranasal Protollin/F1-V vaccine elicits respiratory and serum antibody responses and protects mice against lethal aerosolized plague infection.

F1-V is a recombinant plague antigen comprising the capsular (F1) and virulence-associated (V) proteins. Given intramuscularly with Alhydrogel, it protects mice against challenge, but is less effective in non-human primates against high-dose aerosolized Yersinia pestis challenge, perhaps because it fails to induce respiratory immunity. Intranasal immunization of mice with F1-V formulated with a Proteosome-based adjuvant (Protollin), elicited high titers of specific IgA in lungs whereas intranasal F1-V alone or intramuscular Alhydrogel-adsorbed F1-V did not. The Protollin-adjuvanted F1-V vaccine also induced high serum titers of specific IgG, comparable to those induced by intramuscular Alhydrogel-adsorbed F1-V. Mice immunized intranasally with Protollin-F1-V were 100% protected against aerosol challenge with 170 LD50 of Y. pestis and 80% against 255 LD50.

Safety and immunogenicity of a Proteosome -trivalent inactivated influenza vaccine, given nasally to healthy adults.

We studied the safety and immunogenicity of a nasally administered vaccine comprising three monovalent inactivated influenza antigens (A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Guangdong/120/2000) non-covalently associated with outer membrane proteins of Neisseria meningitidis (Proteosome) in normal, healthy adults. In a randomized, double-blind trial participants (n = 78) were allocated to placebo or a single nasal dose of vaccine containing 15, 30, or 45 microg of each of the three HA antigens, or two nasal doses containing 30 microg of each HA, separated by 2 weeks. The vaccine was generally well tolerated in all doses tested, and in a one or two-dose schedule. A shallow vaccine reactogenicity dose-response was seen. The most common local reaction was nasal congestion, which occurred in up to 48.3% of vaccine recipients in days 0-6 after vaccine but was mild and self-limiting; this reaction was not significantly more common among active vaccine recipients than placebo recipients. Mild to moderate headache was the most commonly reported systemic reactogenicity complaint in all treatment groups, and was the only solicited complaint to increase significantly in frequency after a second active dose. No severe systemic reactions occurred. A positive and statistically significant antibody response was observed, in serum and in nasal secretions, to increasing dose for all three antigens. Serum HAI titre responses and nasal secretory IgA immune responses were elicited against all three antigens. Further testing of this nasal influenza vaccine is warranted to determine its safety and immunogenicity in these populations and its efficacy in the prevention of clinical illness.

Boostrix (GlaxoSmithKline).

GlaxoSmithKline plc has developed and launched Boostrix, a subunit vaccine for use in adolescents and adults as a booster immunization against diphtheria, tetanus and pertussis (DTPa) infections.

Peru-1 5 (AVANT).

Peru-15 is a single dose, recombinant cholera vaccine under development by AVANT Immunotherapeutics for the potential prevention of cholera. A phase II trial of Peru-15 was ongoing in June 2003, and as of September 2003 AVANT was planning a phase III trial in a developing country, and phase IIb and phase III challenge studies in travelers.

Technology evaluation: ChimeriVax-DEN, Acambis/Aventis.

Acambis, in collaboration with Aventis Pasteur, is developing a chimeric vaccine based on a recombinant yellow fever vaccine for the potential prevention of dengue virus infection. The vaccine is undergoing phase I clinical trials.

Protollin: a novel adjuvant for intranasal vaccines.

Protollin is a novel adjuvant comprising Proteosomes non-covalently complexed with LPS. Intranasal immunization of mice with Protollin combined with detergent-split influenza antigens (HA) or recombinant influenza hemagglutinin (rHA) enhanced serum IgG and mucosal IgA levels by up to 250-fold compared with immunization with the antigens alone. IFN-gamma responses were also enhanced compared to the levels produced by splenocytes from mice immunized with antigen alone, while production of IL-5 was abrogated. Mice immunized with Protollin-rHA were completely protected against lethal challenge with influenza virus, demonstrating that Protollin is an effective mucosal adjuvant for prophylactic vaccines.

A chimeric live attenuated vaccine against Japanese encephalitis.

Japanese encephalitis is a disease of the CNS, endemic in Asia and Oceania. The disease is refractory to drug treatments and whilst the rural economies remain heavily dependent on agriculture, conditions for propagation of the disease will persist. Thus, there is a need for effective vaccines. Although some currently exist, they have their shortcomings. ChimeriVax-JE (Acambis Inc.) is a chimeric, live attenuated vaccine which expresses protective Japanese encephalitis antigens and to date has proven to be safe, effective and well-tolerated in clinical trials. It therefore appears to be a cost-effective prophylactic vaccine against this debilitating disease.

ChimeriVax-JE. Acambis.

Acambis (formerly Peptide Therapeutics Group) is developing a vaccine for the potential prophylaxis of Japanese encephalitis (JE) virus infections. In August 2001, Acambis commenced a phase II trial of its ChimeriVax-JE vaccine; these studies were complete by February 2002 and the company was making plans to begin an additional phase II study in children living in areas where JE is prevalent. By May 2003, Acambis had initiated a phase II trial in Australia.