The year 2013 marked the fiftieth anniversary of the licensure (in March 1963) of the live attenuated measles virus vaccine which has been administered worldwide to several billion infants and children, reducing the annual mortality from this infection from an estimated 6 million to 158 000 in 2011. Developed in the laboratory of Nobel laureate John F Enders by a research team, the Edmonston measles virus [named for the youngster, David Edmonston, from whom it was isolated (in some contrast to Salk’s and Sabin’s poliovirus vaccines)]1 was cultivated in primary human kidney cells, then human amnion cells, later embryonated hens’ eggs and lastly in chick embryo fibroblasts. The kidney-passaged virus, when inoculated into susceptible cynomolgous monkeys, produced a clinical illness with rash and fever, viraemia and measles antibodies.2 In contrast, the chick fibroblast virus3 produced measles-specific antibodies in the absence of illness or viraemia. Katz challenged the latter monkeys with the early kidney virus, to which they proved totally resistant–immune. Intracerebral inoculation of the kidney-propagated virus produced remarkable lesions whereas the chick fibroblast virus resulted in no histological changes. Heartened by these results, we then inoculated adults with the chick virus, which produced no lesions or systemic aberrations.4 With institutional permission and agreement from their parents, we administered the virus to susceptible children in a facility housing children with varied disabilities where measles outbreaks with significant morbidity, and some mortality, occurred every 2 or 3 years. The children were examined daily and throat and blood cultures showed no viraemia or pharyngeal virus, but measles-specific antibodies were demonstrable within 10–14 days. Some of them had a day or two of fever followed by an evanescent rash, but no disability.5 In subsequent institutional outbreaks of measles over the next years, these recipients remained totally well without any signs or symptoms of measles. This then established the efficacy of the Edmonston chick cell virus, resulting in a usable vaccine.
The success of the measles vaccine
With these encouraging results, we mobilized a number of paediatric clinical investigators throughout the USA in a number of cities (New Haven, Boston, Baltimore, Denver, Cleveland and New York) to collaborate in administering the Edmonston vaccine virus to normal home-dwelling children, in whom similar results were observed and assessed.6 With the publication of these results, there was rapid uptake of the vaccine by many paediatric groups with the eventual accumulation of sufficient data on safety, immunogenicity and prophylactic efficacy in more than 25 000 children to warrant licensure in March 1963.
Although measles in the USA occurred in more than 90% of children by the age of 8 years, and complications (most often pneumonia or diarrhoea, rarely encephalitis) requiring hospitalization in up to 20%, mortality was rare (1 in 400). In contrast, measles in children in many of the resource-poor nations (e.g. sub-Saharan Africa) was a major cause of both morbidity and mortality (5–15%). At the urging of Dr David Morley, a British physician working in Nigeria, Katz joined him there and studied the Edmonston vaccine in Nigerian children. Protein and vitamin A deficient, malaria infected and intestinal worm colonized, these were the youngsters susceptible to measles and its complications resulting in such high hospitalization and fatality rates among the resource poor. Their sore mouths from the glossitis of measles discouraged their oral intake of breast milk, while their enteritis resulted in excess fluid loss from diarrhoea, producing dehydration, an additional liability. Fortunately, the Edmonston vaccine proved equally innocuous and immunogenic in these recipients.7
With the widespread demonstration of the vaccine’s efficacy and its licensure, we then took a leadership role in its advocacy and establishment of national programmes in the USA, through the Committee on Infectious Diseases and the Red Book Committee of the American Academy of Pediatrics, the Advisory Committee on Immunization Practices of the Centers for Disease Control and a number of National Institutes of Health and Institute of Medicine committees and councils. With the requirement of the school entry measles vaccination, measles rapidly declined over the next decades until there were outbreaks in 1989–91 among the 5–10% of youngsters who had failed to develop immunity after their initial solitary dose of vaccine. This then led to the highly successful two-dose schedule, so that by the year 2000 measles was declared eliminated from the USA.8 Cases in the subsequent years, nearly all among unvaccinated children, have resulted from importation from countries in Europe, Asia and Africa with continuing measles endemicity. Meanwhile, programmes of the Pan American Health Organization were able to eliminate measles from Middle and South America so that by 2002 it was possible to state that the entire western hemisphere was free of the disease.9
The expansion of the measles vaccine
Since 1974, the World Health Organization (WHO) has included measles vaccine in its Expanded Program of Immunization (EPI), resulting in a marked reduction in measles morbidity and mortality where the programme has been introduced. In all countries, Edmonston vaccine derivatives have been used except in Russia, China and Japan, which have developed their own vaccines. Prior to EPI, annual childhood deaths from measles are estimated to have exceeded several million globally. Nevertheless, by the year 2000 WHO estimated that annually more than 700 000 children still died of measles and its complications.10 Recognizing this unacceptable continuing toll due to a vaccine-preventable disease, the Measles Initiative (MI) was started by the American Red Cross in 2001 joined by the international Red Cross organizations, WHO, Centers for Disease Control and Prevention, UNICEF and the United Nations Foundation. Over succeeding years, more than 15 additional national and international organizations have joined the original five in their efforts. MI has organized and supported programmes throughout sub-Saharan Africa and parts of Southeast Asia, distributing more than one billion doses of vaccine, resulting in a 71% reduction in measles mortality in the first decade, with an estimated 150 000 deaths in 2011. Many of its campaigns have combined measles vaccinations with other child health benefits, including oral polio vaccine, vitamin A administration, antihelminth medications, oral rehydration kits for those with diarrhoea, insecticide-impregnated bed nets, iron and folic acid for pregnant women as well as tetanus toxoid vaccination for women of child-bearing age.
The rubella vaccine
In recognition of the tragic consequences of early pregnancy infections with rubella, estimated to result in more than 100 000 annual cases of blindness, deafness, congenital heart defects and central nervous system deficits, the MI in 2012 broadened its goals to include elimination of rubella virus infections and thus became the Measles-Rubella Initiative. Ready availability of the relatively inexpensive combined measles and rubella vaccines (MR) ensures the eventual achievement of this added goal.11 Many countries have employed MR or measles, mumps and rubella (MMR) vaccines beginning with their availability in the 1970s, but these have not been used in most of the resource-poor nations, of which, even now, only a handful (Rwanda, Ghana, Cape Verde, Senegal) have begun to introduce the MR vaccine. A favourable feature of the Polio Eradication Program has been WHO’s addition of measles and rubella virus technology to its international laboratory network, enabling the ready availability of investigation of alleged measles or rubella cases to determine their aetiology and to trace transmission pathways. Viruses can be identified and genotyped from oral fluids or filter paper-dried blood spots.
Fortunately, the measles vaccine of 1963 has proven efficacious over these 50 plus years against the 23 recognized genotypes of measles virus throughout the world, despite shifts in content and structure of circulating strains of virus.12 In addition, the persistence of immunity without boosters, or exposure to natural infections, has been heartening and suggestive of possible lifelong protection from vaccination. The continuing problems of measles morbidity and mortality are not the result of vaccine failures – they are attributable to the remaining large numbers (possibly 22 million) of unvaccinated infants and children mainly among disadvantaged populations. Regrettably, however, the very success of vaccination in countries where elimination had nearly been achieved has resulted in complacency and relaxation of efforts as well as enhanced vaccine hesitancy among some parents, so that reintroduction of this most highly transmissible virus has kindled new outbreaks. A distressing graphic example is the outbreaks that have occurred in several European countries these past 5 years, with more than 25 000 cases each year in 2010, 2011, 2012, 2013. (Resultant importations to the western hemisphere have originated from England, France, Spain, Italy, Germany, Switzerland, Ukraine, Bulgaria and Romania.) These failures in countries well able to maintain effective control and elimination programmes have only added to the challenges of sub-Saharan Africa and Southeast Asia, where major outbreaks still occur and persist owing to weak health systems, lack of federal commitment, inadequate funds, migrations and mobility of large populations, natural disasters such as major floods and, most recently, armed conflicts.
Only smallpox and the animal virus rinderpest13 have been successfully eradicated. Although the polio eradication effort was initiated in 1988 and intended to be completed in 2000, 14 years later it remains incomplete despite the expenditure of billions of dollars and the countless efforts of innumerable dedicated persons internationally, including some recently murdered vaccine workers and their security officers.14 Like smallpox, measles is a product of a single virus, results in a distinct well-recognized rash in nearly all those infected and the infectious virus is excreted for less than 2 weeks. Polio, in contrast, produces overt disease in less than 1 in 200 of those infected, but all of whom excrete transmissible virus for as many as 3 weeks or more. Might measles have proven a more likely successful successor to smallpox eradication rather than polio?