The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study.

BACKGROUND: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. METHODS AND FINDINGS: The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%-25% (all simulations: -3%-34%) and in high-transmission settings (SP9 ≥ 70%) by 13%-25% (all simulations: 10%- 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines. CONCLUSIONS: Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine.

Expanding the recommendations for annual influenza vaccination to school-age children in the United States.

BACKGROUND: Despite long-standing recommendations to vaccinate children who have underlying chronic medical conditions or who are contacts of high-risk persons, vaccination coverage among school-age children remains low. Community studies have indicated that school-age children have the highest incidence of influenza and are an important source of amplifying and sustaining community transmission that affects all age groups. METHODS: A consultation to discuss the advantages and disadvantages of a universal recommendation for annual influenza vaccination of all children age ≥6 months was held in Atlanta, Georgia, in September 2007. Consultants provided summaries of current data on vaccine effectiveness, safety, supply, successful program implementation, and economics studies and discussed challenges associated with continuing a risk- and contact-based vaccination strategy compared with a universal vaccination recommendation. RESULTS: Consultants noted that school-age children had a substantial illness burden caused by influenza, that vaccine was safe and effective for children aged 6 months through 18 years, and that evidence suggested that vaccinating school-age children would provide benefits to both the vaccinated children and their unvaccinated household and community contacts. However, implementation of an annual recommendation for all school-age children would pose major challenges to parents, medical providers and health care systems. Alternative vaccination venues were needed, and of these school-located vaccination programs might offer the most promise as an alternative vaccination site for school-age children. CONCLUSIONS: Expansion of recommendations to include all school-age children will require additional development of an infrastructure to support implementation and methods to adequately evaluate impact.

Vaccine candidates derived from a novel infectious cDNA clone of an American genotype dengue virus type 2.

BACKGROUND: A dengue virus type 2 (DEN-2 Tonga/74) isolated from a 1974 epidemic was characterized by mild illness and belongs to the American genotype of DEN-2 viruses. To prepare a vaccine candidate, a previously described 30 nucleotide deletion (Delta30) in the 3' untranslated region of DEN-4 has been engineered into the DEN-2 isolate. METHODS: A full-length cDNA clone was generated from the DEN-2 virus and used to produce recombinant DEN-2 (rDEN-2) and rDEN2Delta30. Viruses were evaluated for replication in SCID mice transplanted with human hepatoma cells (SCID-HuH-7 mice), in mosquitoes, and in rhesus monkeys. Neutralizing antibody induction and protective efficacy were also assessed in rhesus monkeys. RESULTS: The rDEN2Delta30 virus was ten-fold reduced in replication in SCID-HuH-7 mice when compared to the parent virus. The rDEN-2 viruses were not infectious for Aedes mosquitoes, but both readily infected Toxorynchites mosquitoes. In rhesus monkeys, rDEN2Delta30 appeared to be slightly attenuated when compared to the parent virus as measured by duration and peak of viremia and neutralizing antibody induction. A derivative of rDEN2Delta30, designated rDEN2Delta30-4995, was generated by incorporation of a point mutation previously identified in the NS3 gene of DEN-4 and was found to be more attenuated than rDEN2Delta30 in SCID-HuH-7 mice. CONCLUSIONS: The rDEN2Delta30 and rDEN2Delta30-4995 viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine.

Vaccination of calves against bovine herpesvirus-1: assessment of the protective value of eight vaccines.

Eight separate, but related experiments, were carried out in which groups of six calves were vaccinated with one of eight commercial vaccines. In each experiment the vaccinated calves were subsequently exposed to three calves infected with virulent bovine herpesvirus-1 (BHV-1). In each experiment, all infected donor calves developed a typical severe infectious bovine rhinotracheitis (IBR) infection and excreted virus in their nasal secretions of up to 10(8.00) TCID50/0.1 ml. One live BHV-1 gE-negative vaccine (A) and three modified live vaccines (B, C, D), administered intranasally, all protected against clinical disease. The calves vaccinated with one vaccine (C) also did not excrete virus in the nasal secretions, whereas the calves protected by vaccines A, B and D excreted virus in their nasal secretions but at low titres (10(0.66)-10(1.24) TCID50/0.1 ml). A fourth modified live vaccine (E), given intramuscularly, failed to prevent mild clinical disease in the calves which also excreted virus in the nasal secretions at titre of 10(1.00) TCID50/0.1 ml. An analogous result was given by the calves vaccinated with either of the two inactivated vaccines (F and G) or with a BHV-1 subunit vaccine (H). All calves developed mild clinical signs and excreted virus at titres of 10(2.20)-10(3.12) TCID50/0.1 ml. Calves vaccinated with C vaccine were subsequently given dexamethasone, following which virus was recovered from their nasal secretions. The virus isolates did not cause disease when calves were infected and appeared to be closely related to the vaccine strain.

Cold-attenuated live influenza vaccines, a risk-benefit assessment.

The principle of live attenuated influenza vaccines has been known for many decades. However, the pharmaceutical and clinical development according to current regulations, of modern live influenza vaccines based on cold adapted influenza viruses (CAIV) started only recently and these vaccines will most probably become an alternative within the next couple of years to licensed inactivated influenza vaccines that have been used routinely since the early 1940s. In contrast to contemporary trivalent inactivated influenza vaccines, which are administered intramuscularly, trivalent CAIV-based vaccines will be administered intranasally as a spray. Quality, safety and efficacy aspects related to CAIV vaccines as well as possible risks linked to the widespread use of these vaccines will be discussed in the following overview and compared to established influenza vaccines. Moreover, issues of practicality of CAIV vaccines focusing on the necessity of an annual update of influenza vaccines are addressed.

Current status and future trends in vaccine regulation--USA.

In regulating vaccines, the US Food and Drug Administration (FDA) is governed by the Code of Federal Regulations. These regulations serve as the framework for product characterization, as well as preclinical and clinical testing strategies. Novel vaccine approaches such as combination vaccines, vectored vaccines, new adjuvants, and novel delivery systems pose unique regulatory challenges for the FDA. If US licensure is sought, communication with the FDA throughout the clinical development of a product is essential to identify and implement the appropriate strategies for demonstrating the safety and effectiveness of a new product.

Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines.

Although an effective killed virus vaccine to prevent illness due to Japanese encephalitis virus (JEV) infection exists, many authorities recognize that a safe, effective live JEV vaccine is desirable in order to reduce the cost and the number of doses of vaccine required per immunization. A large-scale clinical efficacy trail for such a vaccine would be both unethical and impractical. Therefore, a surrogate for the efficacy of JE vaccines should be established. Detection of virus-neutralizing antibodies in sera of vaccinees could constitute such a surrogate for efficacy. Field studies of vaccinees in endemic areas and studies done in mice already exist to support this concept. Also, titers of virus-neutralizing antibodies are already accepted as a surrogate for the efficacy of yellow fever virus vaccines and for the efficacy of other viral vaccines as well. In developing a correlation between N antibody titers and protection from JEV infection, standard procedures must be validated and adopted for both measuring N antibodies and for testing in animals. A novel live virus vaccine could be tested in the mouse and/or the monkey model of JEV infection to establish a correlation between virus-neutralizing antibodies elicited by the vaccines and protection from encephalitis. In addition, sera of subjects receiving the novel live JEV vaccine in early clinical trials could be passively transferred to mice or monkeys in order to establish the protective immunogenicity of the vaccine in humans. A monkey model for JEV infection was recently established by scientists at WRAIR in the US. From this group, pools of JEV of known infectivity for Rhesus macaques may be obtained for testing of immunity elicited by live JE vaccine virus.

Recent development in control of Theileria annulata in Iran.

During 1973-1990 cattle immunization, in Iran, was induced by two strains within an interval of one month: first the milder and then the mild strain. Although this method of vaccination rendered satisfactory results in the field, yet production, maintenance in deep-freezers and transportation in liquid nitrogen particularly to remote areas of the country proved to be uneconomical and time consuming. Therefore, in order to reduce cost and save time, a new method involving only one local and live attenuated vaccine strain was sought. Reports received from different ecological areas of the country have shown no presence of any significant abnormal side-effects in vaccinated cattle and the immunization results have been highly satisfactory.

Vaccines for bluetongue.

Isolation of 8 serotypes of bluetongue virus (BTV) in Australia has led to widespread debate on how to prepare for an outbreak of bluetongue disease and the type of vaccine best suited to control bluetongue in Australia. This article describes the vaccine options under consideration by research workers and animal health administrators. The most widely discussed options are live attenuated virus, killed virus and virus-like particles (VLP) generated by recombinant baculoviruses. Attenuated virus vaccines are cheap and easy to produce and are administered in a single dose. They replicate in sheep without causing significant clinical effects and provide protection against challenge with virulent virus of the same serotype. The possibility that insects could acquire vaccine virus by feeding on vaccinated animals and transmit it to sheep or cattle cannot be eliminated. This poses a risk because attenuated viruses are teratogenic if ewes are infected in the first half of pregnancy. In addition, vaccine virus replication in insects and ruminants may lead to a reversion to virulence. Killed virus vaccines have been shown to be efficacious in small laboratory trials and cannot be transmitted to other animals in the field, but are significantly more expensive to produce than attenuated viruses and require at least 2 doses with adjuvant to elicit an immune response. More work is needed to properly assess their effectiveness and determine their cost of production. Recombinant VLP contain the 4 major structural proteins of BTV but no nucleic acid. VLP are relatively easy to isolate, but it is unlikely that the purification methods currently used in laboratories will be adapted for use commercially. Despite the enthusiasm of recent years, little commercial progress appears to have been made. Although scientific research in Australia and overseas has provided a number of options for development of bluetongue vaccines, the decisions on which to use in an outbreak are complex and will require, not only consideration of factors discussed here, but also agreement from industry and government.

Experience with veterinary vaccines in warm climates.

After a short description of the African laboratories manufacturing veterinary vaccines, the authors explain the main constraints for the use, in the field, of veterinary vaccines in warm climates. The need to respect the cold chain from the supplier of vaccines to the recipient animal is emphasised. In the Ivory Coast, during national vaccination campaigns, it has been proved that the quality of the rinderpest and contagious bovine pleuropneumonia vaccines is satisfactory when there is no disruption in the cold transport services. The data of this survey are exposed. In the framework of a project entitled "Thermostable rinderpest Vaccine, Transfer of Technology", a thermostable vaccine has been developed. It is manufactured in different African laboratories and integrated in some Pan African Rinderpest Campaign (PARC) vaccination programmes. On the other hand, the prospects offered by new thermotolerant attenuated vaccines against Newcastle disease are exposed. Finally, the authors present an outlook on the development of thermoresistant veterinary vaccines, such as those produced by genetic engineering, in particular with pox virus vectors.

Licensing and control authority batch release of influenza vaccine in Germany in accordance with EEC regulations.

The epidemiological situation calls for almost yearly changes in the antigenic composition of influenza vaccine, thus necessitating fresh licensing procedures. Since the time for bringing a new vaccine onto the market should be relatively short, the following work of all parties involved must be done expeditiously: 1) WHO recommendations on new virus strains and their subsequent adaptation by the EEC (February/March); 2) Distribution of the new virus strains to the International Reference Centers for Influenza in the UK and USA (February/March); the centers later issue reference materials for the determination of the haemagglutinin antigen concentration (April/May); 3) Production and testing of seed virus by manufacturers, as well as validation of the producer's inactivation process for the new virus strains (May/June); 4) Licensing of the vaccines by the National Control Authority (Paul-Ehrlich-Institute) (June/July); in the case of previously licensed products, the procedure is limited essentially to the approval of the detailed protocol of production and tests on the new virus strains, clinical studies not being required before licensing because of a lack of time; 5) Paul-Ehrlich-Institute's test for batch release, according to Directive 89/342/EEC, besides protocol approval, conducts material testing of the endotoxin and antigen content of each vaccine lot; the assay for the antigen quantification is especially laborious and sometimes must be repeated because of test invalidity.

The suitability of a rolled BHK21 monolayer system for the production of vaccines against the SAT types of foot-and-mouth disease virus. I. Adaptation of virus isolates to the system, immunogen yields achieved and assessment of subtype cross reactivity.

In an examination of 34 southern African SAT-type foot-and-mouth disease viruses, all but 1 attained satisfactory levels of infectivity within 6 passages in rolled BHK21 monolayer cell cultures. However, there were marked differences between adapted viruses with respect to the mass of immunogen (146S material) produced. Several isolates which consistently produced levels greater than or equal to 2 micrograms/ml were identified. In cross neutralization tests using post-vaccinal sera, SAT-1 and SAT-2 isolates showed considerable diversity and none of the viruses tested would be expected to produce a broad-spectrum response if incorporated into a vaccine. On the other hand, when 2 of the SAT-2 isolates were incorporated into the same vaccine a distinctly broader response resulted.

The infant rat as a model for assessment of the attenuation of human influenza viruses.

The intranasal infection of infant rats with Haemophilus influenzae type b can be considerably enhanced by prior infection of the rats with influenza virus. When influenza virus A/England/939/69 was used to infect the animals a minimum of 10(4-0) EID50 was required to enhance H. influenzae infection; infection with 4 x 10(6) H. influenzae bacteria was needed to reveal this enhancement and infant rats two days old at the time of virus inoculation had to be used. By this method, nine strains of influenza virus were assessed for their ability to enhance H. influenzae infection, and the results were compared with their known virulence for man. The results showed a close correlation in this respect for all of the viruses, except strain A/PR/8/34. The replication of these viruses in infant-rat turbinates and lungs was also studied; virus concentrations in turbinate tissues 48 h after infection showed a close correlation with virulence for man. Thus, three influenza virus strains known to be virulent for man reached concentrations in infant-rat turbinates ranging from 10(4-8) to 10(5-7) EBID50/0-05 ml at 48 h; the concentrations of six viruses known to be attenuated or non-infectious for man grew less well in infant rat turbinates, and reached concentrations at 48 h of 10(1-0) to 10(3-5) EBID50/0-05 ml. The results are discussed in relation to the use of the infant-rat model for assessment of the attenuation of candidate live influenza virus vaccine strains.

Production and control of live oral poliovirus vaccine in WI-38 human diploid cells.

Production of live poliomyelitis vaccine in human diploid cells WI-38 can be carried out successfully on a continuous basis. Starting at the 8th population doubling level it is possible to produce 128 ampoules, each containing 1 ml of cell suspension at the 16th level. Each of these cell seed ampoules will yield 85 bottles each with a surface area of 1400 sq. cm at the production level (P29) together with 85 Roux bottle cultures which act as controls. A further passage from the control cells yields a sufficient supply of cells for karyology, tumourigenicity and other tests. Virus yields of the Sabin strains are rather lower than those obtained in primary monkey kidney cells, but this is compensated for by the very much lower reject rate. Karyological characterisation is undoubtedly the most demanding of the testing procedures both in time and expertise. Other tests for contamination, other than bacteriological have yielded uniformly negative results. There is urgent need for standardization of the assay systems used in different laboratories and there is perhaps a case for the use of reference vaccine produced in homogeneic cells.

Production and control of rabies vaccines made on diploid cells.

Introductory remarks on the advantages of antirabies vaccines obtained from human diploid cell cultures in comparison with brain tissue vaccine and duck embryo vaccine. The characteristics of these new types of vaccine are: (i) high antigenicity, (ii) rapid development of antibodies, (iii) absence of adverse reactions even when the booster inoculation was given two years later. The disadvantage is the high cost of production to obtain a highly purified product.