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.

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.

Resiquimod 3M.

3M Pharmaceuticals is developing a topical formulation of resiquimod as an immunomodulator for the potential treatment of herpes simplex virus (HSV) infections. As of September 2001, resiquimod was to be commercialized worldwide in association with Eli Lilly. Phase III trials for the treatment of HSV infection were initiated in November 2000 and were ongoing in September 2001. In October 2001, US and European filings were scheduled for 2004, and by February 2002, Lilly was anticipating launch in either 2004 or 2005. The compound has also been investigated for the potential treatment of various other diseases, including other viral infections and eczema and as a vaccine adjuvant.

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.

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.

Hepagene (PowderJect).

Celltech Group (formerly Medeva) developed Hepagene, a recombinant polyvalent vaccine with potential activity against hepatitis B virus infections [353474]. In September 2000, PowderJect acquired the product as part of its acquisition of Celltech's vaccine manufacturing business [381557]. In July 2001, PowderJect reported that evaluation was nearing completion. At this time, the company expected to launch the vaccine in the coming months [443490]. Hepagene is a polyvalent vaccine with S, pre-S1 and pre-S2 hepatitis B epitopes forming the basis of its antigenicity. Additionally, these surface markers have been glycosylated in order to resemble the live virus more closely [254780]. By June 2000, Celltech and PowderJect were evaluating Hepagene, utilizing PowderJect's needle-less injection technology [379536]. In December 1999, Lehman Brothers predicted that the product had a 50% chance of reaching the treatment (rather than prevention) market, with potential peak sales of US $600 million [352078].

StaphVAX (Nabi).

StaphVAX is a bivalent polysaccharide- and protein-conjugated vaccine, directed against capsular Staphylococcus aureus types 5 and 8, which are associated with 80 to 90% of S aureus clinical infections. The vaccine is being developed by Nabifor the potential treatment of infections in kidney patients who are receiving peritoneal dialysis and are prone to serious staphylococcal infections [193495], [221403], [222643], [283114]. In February 2001, Nabi revealed that it was movingforward during the second quarter of 2001 with previously stated plans to conduct a boosting study of StaphVAX in patients with end-stage renal disease (ESRD). This study would be conducted in patients who were enrolled in the first phase III trial and the company expected completion by early 2002 [283114]. The company was also progressing with scale-up of the manufacturing process for commercial production of the vaccine. Nabi met with the FDA in December 2000 to review results from its phase III trial of StaphVAX in patients with ESRD. The FDA stated that a definitive demonstration of preventative efficacy in another well-designed, randomized and controlled clinical study would be required for licensing. At this time, Nabi was making plans for this second phase III trial, despite plans to appeal the FDA's decision [397729].

Varivax (Merck & Co).

Varivax is a live-attenuated varicella vaccine developed and launched in the US by Merck & Co for the treatment of chickenpox [413319]. The vaccine uses the Oka strain of the varicella virus licensed from the Biken Institute at Osaka University in Japan [178223]. By June 2001, Merck was also developing the vaccine for use in adults for herpes zoster infection [413319]. The FDA required post-marketing studies as a condition for its approval of Varivax, which was granted in March 1995 [174416]. The Centers for Disease Control & Prevention Advisory Committee on Immunization Practices recommended that Varivax should be administered at the same time as the measles, mumps and rubella vaccine. Unvaccinated children between the ages of 19 months and 13 years should be vaccinated by the time they are 13 years old [180148]. Varivax, from its launch in the spring of 1995 to the end of the third quarter 1995, produced sales of US $60 million [196542]. In June 2000, a second generation of Varivax, Varivax II, was launched for vaccination against chickenpox in individuals 12 months of age and older. Varivax II prevents the transmission of chickenpox with exactly the same safety and efficacy profile as Varivax; however, the new Varivax II has the advantage of being refrigerator-stable [371871].

Remune. Immune Response.

The Immune Response Corp (IRC) is developing Remune, a potential HIV therapeutic vaccine. Remune is based on the Salk Immunogen, which is derived from an HIV isolate which has been inactivated by chemical depletion of glycoprotein 120 (gp120). Preliminary data suggested that Remune, in combination with antiviral drug therapy, results in undetectable levels of HIV. Phase III trials commenced in May 1997 and it was initially expected that registration filings would be made in 1999. However, following interim analysis of the 2500-patient, multicenter, double-blind, pivotal phase III study (study 806) in May 1999, an independent panel recommended concluding the clinical endpoint trial and IRC and licensee, Agouron, decided to pursue alternative regulatory strategies, including initiating two additional phase III surrogate marker trials. Despite this, Agouron gave IRC notice of termination of its continued development in July 2001. In August 2001, IRC informed Agouron that, due to the total number of endpoints to date falling short of that previously assumed by Agouron, it did not intend to continue Agouron's Study 202 of Remune. In July 2001, licensee Trinity Medical Group filed an NDA with the governing health authorities in Thailand for Remune. The Thai FDA certified Immune Response's Remune manufacturing facility as being in compliance with GMP standards, following an on site inspection by Thai officials in November 2001 that was performed as a requirement of Trinity's Thai NDA. As a result of this certification, Trinity expected that a "timely determination" could be made by the Thai FDA. Rhjne-Poulenc Rorer discontinued its part in the development of Remune, with all manufacturing, marketing and distribution rights reverting to IRC. After Agouron returned rights to Remune in July 2001, IRC heldfull rights in the US, Europe and Japan, while collaborating with its partners Trinity Medical Group and Roemmers Laboratory in the Southeast Asian and Latin American markets, respectively. In June 1998, Merrill Lynch had expected an FDA filing for Remune by the end of 1999, and in May 1999 Agouron was hoping to file an NDA for the use of Remune against AIDS during 2001. Analysts at Lehman Brothers predicted in September 2001, that the product would be launched onto the market with sales of US$150 million in 2004.

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.

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.

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.

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.

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.

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.

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.

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.

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.