The Challenge of Global Poliomyelitis Eradication.

In the United States during the 1950's, polio was on the forefront of every provider and caregiver's mind. Today, most providers in the United States have never seen a case. The Global Polio Eradication Initiative (GPEI), which began in 1988 has reduced the number of cases by over 99%. The world is closer to achieving global eradication of polio than ever before but as long as poliovirus circulates anywhere in the world, every country is vulnerable. The global community can support the polio eradication effort through continued vaccination, surveillance, enforcing travel regulations and contributing financial support, partnerships and advocacy.

Killed but metabolically active vaccines.

Beginning in the 20th century and continuing into the new millennia, vaccines against numerous diseases have had an unquestioned principal role of both enhancing the quality of life and increasing life expectancy (Rappuoli R, Mandl CW, Black S, De Gregorio E: Vaccines for the twenty-first century society. Nat Rev Immunol 2011, 11:865-872). Despite this success and the development of sophisticated new vaccine technologies, there remain multiple infectious diseases including tuberculosis, malaria and AIDS that await an effective prophylactic vaccine. In addition, there have been recent clinical successes among individuals with cancer using vaccine treatment strategies-so-called therapeutic vaccines-that stimulate tumor specific immunity and increase survival (Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al.: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl J Med 2010, 363:411-422). Here we summarize a new class of vaccines termed Killed But Metabolically Active (KBMA). KBMA vaccines are whole pathogenic or attenuated organisms killed through photochemical inactivation and cannot cause disease, yet retain sufficient metabolic activity to initiate a potent immune response. KBMA vaccines have two broad applications. First, recombinant KBMA vaccines encoding selected antigens relevant to infectious disease or cancer can be used to elicit a desired immune response. In the second application, KBMA vaccines can be derived from attenuated forms of a targeted pathogen, allowing for the presentation of the entire antigenic repertoire to the immune system, of particular importance when the correlates of protection are unknown.

A pandemic influenza vaccine in India: from strain to sale within 12 months.

In the event of a highly pathogenic influenza pandemic, the Indian subcontinent would need 1.2 billion doses of vaccine to immunize its entire population, double if two doses were required to assure immunity. Serum Institute of India Limited (SII) thus became one of six initial grantees of the World Health Organization (WHO) technology transfer initiative to create capacity in developing countries to manufacture H5N1 pandemic influenza vaccine. At the outbreak of the A(H1N1) 2009 influenza pandemic, experience gained from the H5N1 project was used to develop a live attenuated influenza vaccine (LAIV), since this was the only option for the level of surge capacity required for a large-scale immunization campaign in India. SII took <12 months to develop and market its LAIV intranasal vaccine from receipt of the seed strain from WHO. As of November 2010, over 2.5 million persons have been vaccinated with Nasovac(®) with no serious adverse reactions or vaccine failure after 3 months' post-marketing surveillance. The product has been submitted for prequalification by WHO for purchase by United Nations agencies. In parallel, SII also developed an inactivated influenza vaccine, and is currently looking to ensure the sustainability of its influenza vaccine manufacturing capacity.

Domestic influenza vaccine production in Mexico: a state-owned and a multinational company working together for public health.

The Mexican Government developed a plan in 2004 for pandemic influenza preparedness that included local production of influenza vaccine. To achieve this, an agreement was concluded between Birmex - a state-owned vaccine manufacturer - and sanofi pasteur, a leading developer of vaccine technology. Under this agreement, sanofi pasteur will establish a facility in Mexico to produce antigen for up to 30 million doses of egg-based seasonal vaccine per year, and Birmex will build a facility to formulate, fill and package the inactivated split-virion influenza vaccine. As at November 2010, the sanofi pasteur facility has been completed and the Birmex plant is under construction. Most of the critical equipment has been purchased and is in the process of validation. In addition to intensive support from sanofi pasteur for the transfer of the technology, the project is supported by the Mexican Ministry of Health, complemented by Birmex's own budget and grants from the WHO developing country influenza technology transfer project.

Development of pandemic influenza vaccine production capacity in Viet Nam.

The Institute of Vaccines and Medical Biologicals (IVAC), a state-owned vaccine manufacturer, initiated research into avian influenza vaccines in the early 1990 s in response to the threat of a highly pathogenic avian influenza pandemic. Successful results from laboratory studies on A(H5N1) influenza virus attracted seed funds and led to participation in the WHO technology transfer project to enhance influenza vaccine production in developing countries. IVAC's goal is to produce 500,000 doses of inactivated monovalent whole-virion influenza vaccine per year by 2012, and progressively increase capacity to more than 1 million doses to protect essential populations in Viet Nam in the event of an influenza pandemic. The WHO seed grants, supplemented by other international partner support, enabled IVAC to build in a very short time an influenza vaccine manufacturing plant under Good Manufacturing Practice and relevant biosafety standards, a waste treatment system and a dedicated chicken farm for high-quality eggs. Much of the equipment and instrumentation required for vaccine production has been installed and tested for functional operation. Staff have been trained on site and at specialized courses which provided comprehensive manuals on egg-based manufacturing processes and biosafety. Following process validation, clinical trials will start in 2011 and the first domestic influenza vaccine doses are expected in 2012.

An international technology platform for influenza vaccines.

Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance.

New vaccine approaches for seasonal and pandemic influenza.

Inactivated influenza vaccines have been available since the late 1940s for the prevention of influenza disease. Based on the available scientific evidence, many public health authorities, including the World Health Organization, recommend annual use of these vaccines for specific populations, including the elderly. Despite these recommendations, actual vaccination uptake rates are very limited in many countries. Influenza vaccine research is confounded by the variable nature of the influenza viruses and annual influenza epidemics and by non-specific clinical diagnostic criteria. These confounding factors complicate evaluation not only of overall vaccine effectiveness, but also of the relative efficacy and effectiveness of different vaccine formulations. This paper summarizes recent advances in the development of seasonal and (pre-)pandemic vaccines, discusses the methodologic constraints on influenza vaccine research, and proposes measures to reduce the level of potential bias and confounding in influenza vaccine research.

Availability of trivalent inactivated influenza vaccine to parents of neonatal intensive care unit patients and its effect on the healthcare worker vaccination rate.

BACKGROUND: Trivalent inactivated influenza vaccine (TIV) is indicated for healthcare workers (HCWs); however, the vaccination rate in this population is estimated at 35%. We implemented a program for the administration of TIV, targeted at parents of neonatal intensive care unit (NICU) patients. OBJECTIVE: To determine the effect of availability of TIV to parents in the NICU on HCW vaccination rates. DESIGN: Questionnaire survey after an intervention-based study. SETTING: Tertiary-care neonatal intensive care unit. PARTICIPANTS: Physicians, nurses, and other NICU-based staff. METHODS: For the 2005-2006 influenza season, parents of NICU patients were screened and administered TIV, if informed consent was obtained. As a consequence, TIV was available 20 hours/day to all staff. Previous vaccination history and comorbidities in HCWs were also assessed. RESULTS: Of 120 neonatal HCWs, 112 (93%) were screened during the 2005-2006 season; 80 (67%) were vaccinated, compared with 49 (41%) prior to the implementation of this program (P < .03, by Student's t test); 54 (45% of the study population, which includes senior neonatologists, fellow and resident physicians, nurses, respiratory therapists, X-ray technicians and clerical staff) received TIV in the NICU, compared with the 17 (14%) of 120 HCWs the previous year; and 20 (46%) of 43 HCWs of the nursing staff were vaccinated in the NICU, whereas only 3 (7%) of 43 HWCs were vaccinated outside the unit. Attending physicians had the lowest vaccination rate, and most cited efficacy and/or side effects in their deferral. Nurses most often refused influenza vaccination because they had a fear of injection. CONCLUSIONS: Administration of TIV in the NICU is an effective means of increasing the vaccination rate among neonatal HCWs. To increase compliance with vaccination, educational efforts for nurses should emphasize the possibility of viral transmission to neonates as motivation for vaccination. Physician-directed efforts should include tolerability of vaccine side effects. Live attenuated influenza vaccine, administered intranasally, should be considered to increase vaccination rates among NICU nurses.

Supplementary statement on hepatitis A prevention.

In a recent statement on the prevention of infections caused by hepatitis A virus (HAV), NACI described the usual indications for use of immune serum globulin (IG) and the newly available inactivated hepatitis A vaccine (HAVRIX, SmithKline Beecham). Subsequently, a more potent vaccine formulation was licensed, permitting a single dose primary immunization of adults. This supplementary statement addresses this development and comments on vaccine use in children.

Vaccine manufacture at the time of a pandemic influenza.

In the event of a major influenza epidemic, the availability of a potent and safe vaccine would be a major concern. The following presentation describes the main features of a flu vaccine manufacturing campaign: beginning with the supply of embryonated eggs, in which the flu viruses are cultivated, through the different steps of vaccine production - egg harvest, purification, inactivation, splitting - down to the final vaccine formulation and aseptic filling in the appropriate containers. In usual times, such a production cycle takes over 70 weeks. In an emergency situation, the manufacturers and the authorities would have to take innovative approaches to minimize such delays. This will inevitably translate into an enormous strain on all the players in such a project, from the egg suppliers to the organisers of the vaccine dispatching and administration. It will result in suboptimal yields and costs. However, facing a massive and urgent need of vaccine, both the authorities and the vaccine manufacturers must work together to supply the necessary doses in time.

Role of the French drug licensing authority in the prevention of influenza pandemics.

The French Drug Agency is responsible for the control and delivery of batch release certificates. In the case of an influenza pandemic, the use of inactivated vaccines, produced according to well-established procedures and controlled according to the European Pharmacopea and FDA requirements, will be strictly dependent on the necessary delays for production and controls. Mutual recognition between the National Control Laboratories in Europe might help in shortening the delays. If new, inactivated vaccines are produced either on cell cultures or by using genetically modified organisms, and if live attenuated vaccines are needed, it would be suitable to organize ad hoc working groups and international collaborative studies in fields of both research and regulation.