In recent years, measles has had a comeback in populations in which effective vaccination programmes had been installed for decades, like in USA, Australia, England, Germany and other European countries [9, 10] This has raised some key questions:
Is the vaccine still efficient?
The live measles vaccine strain, which is commonly applied, has been isolated from a patient and propagated in embryonic chicken cell cultures as long as random mutations have attenuated its pathogenicity. Modern molecular biologic analysis has typed most vaccine viruses as members of the extinct genotype A, derived from the MeV strain Edmonston . In contrast to the highly contagious wild-type virus, the vaccine virus is not infectious to immune-competent individuals, and person-to-person transmission of vaccine virus has never been documented [5, 11]. To our current knowledge, every MeV strain starts the infection process by interaction of envelope glycoprotein H to virus-specific cell receptors, i.e. CD150, which is a signalling lymphocytic activation molecule (SLAM), and CD46, which is an inhibitory complement receptor . Obviously, vaccine MeV has got a crucial mutation in the H gene which reduces its interaction with CD46. More important for the attenuation is the enhanced interferon induction of the vaccine virus in comparison with the wild type . In addition, further mutations in MeV genome may contribute to attenuation. In particular, the L gene might be the target of in vitro artificial virus attenuation. Despite the fact that other MeV genotypes can replace indigenous genotypes , there is no evidence for immune selection of such viruses in homogenously immunised populations. Forming conserved epitopes across genotypes MeV is antigenetically stable (no relevant escape mutants) [30–32]. Antisera from individuals infected decades ago retain the ability to neutralise current wild-type (WT) strains of MeV and vice versa, although with different efficiency. In the recent measles outbreaks, MeV strains of non-A genotypes, in particular type D, have been isolated [33–35]. Nevertheless, they can still be neutralised by anti-H antisera without significant restriction, indicating that the vaccines are still fully effective [30, 31]. The vast majority of measles patients in current outbreaks had not or not been sufficiently vaccinated, especially in terms of the second dose [10, 35, 36].
Are the current vaccination programmes appropriate?
The timing of delivery strategies for the first and second vaccination dose varies across countries and regions. In countries with ongoing transmission, WHO recommends the administration of the first dose at the age of nine months to ensure optimal protection during the susceptible period in infancy. Re-vaccination is recommended in the second year of life (15–18 months)  to booster and prolong a strong immunity as well as to immunise individuals in which the first vaccination has failed (primary vaccine failure, see above). The minimum interval between the first and second dose is one month. Catch-up vaccination is recommended for all children, adolescents and adults, who have not received the first or second dose of MMR vaccine or have lost their vaccination records in most countries. However, in many European countries those catch-up vaccination programmes were not conducted or accepted efficiently. As a result, measles outbreaks are still occurring despite significantly increasing vaccination rates with a majority of adolescents and young adults (up to 40 years of age) being affected, who were mainly not vaccinated against measles or had received only one dose. In addition, a high percentage of this age group is also not naturally immune against measles . This lack of immunity leads to another complex problem: pregnant women of childbearing age, who were not protected against measles themselves, cannot provide vertical protection for their infants . Furthermore, in the current epidemiological situation they are at risk to acquire measles in pregnancy, which is associated with a higher incidence of hospitalisation, measles-related complications (e.g. pneumonitis) including maternal death and adverse pregnancy outcomes like pregnancy loss, preterm birth and low birth weight, but not congenital defects [38–40]. Infections shortly before or after delivery can lead to intrauterine, perinatal or postnatal MeV infections of the newborn, who then have a high risk to develop SSPE due to their immature immune system [5, 8, 41, 42]. Because of all these aspects mentioned above, it has to be discussed, if additional efforts and other vaccination schedules are necessary to close the vaccination gaps .
Other setbacks why successful vaccination programmes were interrupted leading again to large vaccination gaps are catastrophes including life-threatening disease outbreaks like the Ebola epidemic in West Africa and wars (e.g. in Syria). Currently millions of refugees live in crowded camps or are travelling thousands of kilometres through different countries (part of them with ongoing large measles outbreaks, e.g., in Bosnia-Herzegovina, Serbia) to reach Central and Northern Europe. Because of the mass accumulations of migrants and the rapid migration movements, there is a high risk of transmission and wide spread of infectious diseases, especially measles . There is no possibility to vaccinate these masses of refugees during their migration on the transit routes; however, in the accommodating countries like Germany and Austria, the MMR vaccination of refugees has the highest priority, although the organisation of those mass vaccinations is still a big challenge. In parallel, a rapid increase in the MMR vaccination rates of the native population is necessary to reduce the risk of large outbreaks.
How many people must be vaccinated to establish stable herd immunity for the population preventing virus transmission and mediating protection for individuals who are not immune? This depends on the basic reproduction rate (R0), which indicates how many people on average are infected by an initial spreader in a fully susceptible population. For measles, the index has been calculated to be 12–18, which is one of the highest for any human pathogen . This demands that >94 % of a population has to be immune to stop virus spread (and to ensure herd immunity) [5, 9]. This high rate has been reached for smallpox, when the vaccination had been regulated by law in the most countries. Without such regulation, wild poliovirus type 2 (PV-2) has been eradicated. The eradication of PV-3 is nearly reached . However, PV-2 vaccine-derived strains and wild poliovirus type 1 strains are still circulating in some countries (Israel, West Africa, Afghanistan and Pakistan) [45–47]. The basic reproduction rate (R0) of poliovirus was calculated 4–13 . Consequently, an immunity rate of about 85 % was necessary to effectively interrupt virus circulation. This was reached by vaccination against poliovirus type 2, while the rates for poliovirus 1 and 3 have been found to be sometimes lower . However, a worldwide system of surveillance discovers and closes the gaps in all countries in which vaccination is strictly applied. To exceed a vaccination rate of 90 %, without regulation by law, is a big challenge for the public health system and seems like Sisyphean labour. Measles outbreaks happened when this line was underrun. For these reasons, additional efforts are absolutely necessary to increase vaccine acceptance.
Potentially alarming are, however, reports on sporadic cases of overt measles disease amongst adults, who received two doses of measles vaccine decades ago [5, 38, 49–52]. Some of the cases led to further transmission events and occurred typically in countries which have implemented their vaccination programmes early and successfully and thus achieved the WHO elimination goals, i.e. complete elimination of MeV transmission. These cases could indicate that vaccine-induced IgG levels are waning [20, 53, 54] and the immunological memory to MeV is more limited in the absence of wild-type MeV exposure events than thought before. If cases of breakthrough measles due to secondary vaccine failure are seen more often, this should be an incentive to enhance the speed of the elimination process!
How to speed up the elimination process and arouse public opinion? Should vaccination be regulated by law?
After smallpox, no other vaccination has been so far regulated by law globally, since no other ubiquitously spread infectious disease was considered so life-threatening, especially when an anti-infective therapy is missing. The vaccination against smallpox produced many and severe side effects. The more smallpox waned, the more the vaccination was criticised and refused. Although the anti-MeV vaccination produces much less side effects, it becomes more and more neglected or even rejected when—as a consequence of successful vaccination programmes—the dangerous measles complications decline and disappear out of the public attention, while the fear of adverse effects is increasing . Other factors that have an impact on vaccine uptake in countries with high socio-economical standards are complacency, lack of education about the seriousness of the disease and a degree of mistrust in the medical establishment and the pharmaceutical industry [1, 9]. This results in an increasing number of parents, who are sceptical towards vaccination [9, 56, 57]. In opposite to oral vaccines, injections are being perceived as unpleasant for children and parents. Therefore, combining several vaccines in one injection has proven to be a convenient approach. Such a combined vaccine has been introduced for measles, rubella and mumps and has been extended to varicella (MMR, respectively, MMRV vaccine). It has revealed that the immunogenic infectivity of the single attenuated viruses is not impaired . The combined vaccine should be applied not only for the primary immunisation, but also for secondary boosters to close immunity gaps deriving from the first vaccination. It has been proven very effective in elimination of poliomyelitis caused by three immunologically different poliovirus types . Complications of poliovirus infections are no more frequent than those from measles, but patients suffering from side effects such as paralysis are living amongst us as a visible and constant reminder of this issue. In opposite to poliomyelitis, measles are frequently considered as an unpleasant, but healing up disease of children, even by some medical doctors who believe that passed measles strengthens the power of resistance. However, measles impair the immune system for a longer period of time in which other infectious diseases may happen. So, the public attention on measles must be enhanced and kept high aside of current measles outbreaks [9, 10].
Is the measles surveillance system adequate?
Smallpox has been eradicated not only by vaccination, but also by an effective global reporting and surveillance system. Also for measles (and rubella) elimination a rapid, exact and sensitive surveillance system is of major importance. For the national health authorities, it is important that clinically suspected cases were reported rapidly and implemented control measures can be executed immediately. However, the virological surveillance and laboratory performance play an essential role. In countries near elimination, all suspected cases should be routine laboratory confirmed and PCR samples of anti-MeV-IgM-positive samples sent to a national reference laboratory for further investigation. In some cases, interpretation of laboratory results is challenging (e.g. in persons with a recent history of vaccination, false-positive results because of cross-reactivity with other infections, indeterminate test results or positive results for both measles and another virus like Parvovirus B19, Epstein Barr virus or human herpesvirus type 6). For the elucidation of transmission chains, the differentiation of endemic circulation or the importation of MeV strains, differentiation of imported/imported-related measles cases and the interruption of transmission highly sensitive virological and molecular biological test methods (i.e. viral sequencing, genotyping and phylogenetic analyses) are essential tools for the assessment of epidemiological situation [60, 61].
Measles patients are on average most infectious four days before and after the onset of exanthema. Measles are a severe respiratory disease producing epidemiological issues similar to influenza. Global tourism and worldwide migration due to war and poor economic conditions pose additional challenges to the WHO project of measles eradication [9, 62]. Currently, Europe is affected by massive flows of refugees enhancing, in combination with an increasing sceptical attitude of the Central European population towards vaccines, the risk of new outbreaks. Apart from that, in industrial countries, where measles had become rare, doctors are not so familiar with the clinical symptoms. In underdeveloped countries, malnutrition makes measles more severe and prolongs the period of infectivity. It has to be discussed whether immigrants and tropical tourists should be checked on measles immunity by antibody tests. Simple methods focus on oral fluid swabs saving blood sampling. However, with the current large migration streams in Europe, this would be not feasible, but the immediate administration of the MMR vaccine when the refugees reach their target country has a high priority. Reporting obligation has to be established and expanded in the public health system of every country. Modern molecular diagnostic tools are available for rapid tracing infectious chains [33, 63].