D.J. Wood

Effective vaccine safety systems in all countries: A challenge for more equitable access to immunization

Serious vaccine-associated adverse events are rare. To further minimize their occurrence and to provide adequate care to those affected, careful monitoring of immunization programs and case management is required. Unfounded vaccine safety concerns have the potential of seriously derailing effective immunization activities. To address these issues, vaccine pharmacovigilance systems have been developed in many industrialized countries. As new vaccine products become available to prevent new diseases in various parts of the world, the demand for effective pharmacovigilance systems in low- and middle-income countries (LMIC) is increasing. To help establish such systems in all countries, WHO developed the Global Vaccine Safety Blueprint in 2011. This strategic plan is based on an in-depth analysis of the vaccine safety landscape that involved many stakeholders. This analysis reviewed existing systems and international vaccine safety activities and assessed the financial resources required to operate them. The Blueprint sets three main strategic goals to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods: to ensure minimal vaccine safety capacity in all countries; to provide enhanced capacity for specific circumstances; and to establish a global support network to assist national authorities with capacity building and crisis management. In early 2012, the Global Vaccine Safety Initiative (GVSI) was launched to bring together and explore synergies among on-going vaccine safety activities. The Global Vaccine Action Plan has identified the Blueprint as its vaccine safety strategy. There is an enormous opportunity to raise awareness for vaccine safety in LMIC and to garner support from a large number of stakeholders for the GVSI between now and 2020. Synergies and resource mobilization opportunities presented by the Decade of Vaccines can enhance monitoring and response to vaccine safety issues, thereby leading to more equitable delivery of vaccines worldwide.

Interaction of Yellow Fever Virus French Neurotropic Vaccine Strain with Monkey Brain: Characterization of Monkey Brain Membrane Receptor Escape Variants

ABSTRACT Binding of yellow fever virus wild-type strains Asibi and French viscerotropic virus and vaccine strains 17D and FNV to monkey brain and monkey liver cell membrane receptor preparations (MRPs) was investigated. Only FNV bound to monkey brain MRPs, while French viscerotropic virus, Asibi, and FNV all bound to monkey liver MRPs. Four monkey brain and two mouse brain MRP escape (MRPR) variants of FNV were selected at pH 7.6 and 6.0. Three monkey brain MRPR variants selected at pH 7.6 each had only one amino acid substitution in the envelope (E) protein in domain II (E-237, E-260, or E274) and were significantly attenuated in mice following intracerebral inoculation. Two of the variants were tested in monkeys and retained parental neurotropism following intracerebral inoculation at the dose tested. We speculate that this region of domain II is involved in binding of FNV E protein to monkey brain and is, in part, responsible for the enhanced neurotropism of FNV for monkeys. A monkey brain MRPR variant selected at pH 6.0 and two mouse brain MRPR variants selected at pH 7.6 were less attenuated in mice, and each had an amino acid substitution in the transmembrane region of the E protein (E-457 or E-458).

A WHO collaborative study on assays of the antigenic content of inactivated poliovirus vaccines

In the first phase of a two part WHO Collaborative study, fourteen laboratories from ten countries estimated the antigenic content of six trivalent inactivated poliovirus vaccine preparations using in vitro methods. All laboratories used a candidate standard method for D antigen assay (method A) and eight contributed results from established in-house methods (method B). All methods assayed D antigen in an antigen capture ELISA format. Monoclonal antibodies were used as detector reagents in method A and in some laboratories for method B. The average difference in potency estimates for duplicate preparations A and C was used to assess within assay variation. Overall this was found to be 22% and 19% for methods A and B respectively. Within laboratory variation was measured as the geometric coefficient of variation for between assay repeatability. Results for methods A and B, 28% and 26% respectively were again very similar. Variation in potency estimates between laboratories was in the range 2- to 5-fold for most samples and most laboratories irrespective of the method used. However, a maximum 24-fold difference occurred when all results were taken into account. Method A gave significantly enhanced potency estimates for the type 3 component of preparation B, a vaccine shown to be immunogenic in humans in clinical trials, compared to method B. Method A also failed to assay the type 3 component of preparation F which was prepared by inactivation of the Sabin 3 strain of poliovirus. Further work is required to identify monoclonal antibodies, or combinations of monoclonal antibodies, suitable for universal application in D antigen assays of inactivated poliovirus vaccines. Further work is also required to improve control of the antigen-capture ELISA in some laboratories. The second phase of this WHO Collaborative Study evaluated the proficiency of in vivo potency assays. These results together with an evaluation of the correlation of immunogenicity and antigenic assay plus assessment of candidate reference materials will be reported separately.

Antigenic structure of chimeras of type 1 and type 3 polioviruses involving antigenic sites 2, 3 and 4

Chimeric polioviruses have been made in which regions of the type 1 Sabin strain corresponding to antigenic sites 2, 3 and 4 have been replaced by the corresponding regions of the type 3 Sabin strain. Manipulation of one site or a component of it generally did not affect the reactions of the others, suggesting that they form independent structural features. The extent to which the inserted site expressed the antigenic properties of type 3 could be assessed by reaction with polyclonal or monoclonal antibodies, or by immunogenicity. Site 2 could be expressed on infectious virus and site 3 on heated non-infectious virus (C antigen), but not on the native virion. The results are consistent with the view that sites consisting of a continuous sequence of amino acids may be presented on chimeras, whereas more complex sites, such as site 4 or site 3 of the native virion, are transferred less readily from type 3 to type 1.

Antigenic structure of chimeras of type 1 and type 3 poliovirus involving antigenic site 1

Chimeric polioviruses have been prepared in which part of the antigenic site 1-encoding sequence of the Sabin strain of type 1 poliovirus has been replaced by sequences based on those found in the homologous region of the Sabin type 3 strain. The chimeras were analysed for their reaction with polyclonal and monoclonal antibodies raised against type 1 and type 3 viruses, and with polyclonal antipeptide sera, as well as for their immunogenicity in animals. The effectiveness with which the type 3 site was presented antigenically varied in ways which were partially predictable, based on the behaviour of type 3 mutants with monoclonal antibodies. However, other factors were implicated which may include conformational effects and other components of the site in addition to those altered in the chimeras. The ability of the chimeras to induce antibodies reacting with type 3 polioviruses paralleled their antigenic reactivity, and evidence is presented for the induction of strain-specific antibodies.

The second international standard for anti-poliovirus sera types 1, 2 and 3

The Second International Standard for anti-poliovirus sera types 1, 2 and 3 was established by the WHO Expert Committee on Biological Standardization in 1991 on the basis of an extensive collaborative study. Nine laboratories from eight countries participated and all used neutralizing antibody assays. The standard is a human serum pool which contains antibodies to all three poliovirus types and replaces the three previously established monovalent standards which were all hyperimmune monkey sera. The standard was assigned an activity of 25 IU of anti-poliovirus serum (type 1) human: 50 IU of anti-poliovirus serum (type 2) human; and 5 IU of anti-poliovirus serum (type 3) human. The study also showed significant interlaboratory differences in relative potency are observed when human sera are compared to hyperimmune monkey sera. It was therefore recommended that National laboratory references are established from human sera.

Use of human diploid cells in vaccine production

An informal meeting was held at the National Institute for Biological Standards and Control (NIBSC), Potters Bar, U.K. on 24 August 1989 between representatives from industry, the World Health Organisation (WHO) and NIBSC to discuss issues related to the use of human diploid cells (HDC) in virus vaccine production. This record of the discussions and concensus views which emerged are provided to stimulate consideration by a wider audience. A list of participants is given in the Appendix.