The introduction of 'No jab, No school' policy and the refinement of measles immunisation strategies in high-income countries.

BACKGROUND: In recent years, we witnessed a resurgence of measles even in countries where, according to WHO guidelines, elimination should have already been achieved. In high-income countries, the raise of anti-vaccination movements and parental vaccine hesitancy are posing major challenges for the achievement and maintenance of high coverage during routine programmes. Italy and France approved new regulations, respectively in 2017 and 2018, aimed at raising immunisation rates among children by introducing mandatory vaccination at school entry. METHODS: We simulated the evolution of measles immunity profiles in seven distinct countries for the period 2018-2050 and evaluated the effect of possible adjustments of immunisation strategies adopted in the past on the overall fraction and age distribution of susceptible individuals in different high-income demographic settings. The proposed model accounts for country-specific demographic components, current immunity gaps and immunisation activities in 2018. Vaccination strategies considered include the enhancement of coverage for routine programmes already in place and the introduction of a compulsory vaccination at primary school entry in countries where universal school enrolment is likely achieved. RESULTS: Our model shows that, under current vaccination policies, the susceptible fraction of the population would remain below measles elimination threshold only in Singapore and South Korea. In the UK, Ireland, the USA and Australia either the increase of coverage of routine programmes above 95% or the introduction of a compulsory vaccination at school entry with coverage above 40% are needed to maintain susceptible individuals below 7.5% up to 2050. Although the implementation of mandatory vaccination at school entry would be surely beneficial in Italy, strategies targeting adults would also be required to avoid future outbreaks in this country. CONCLUSIONS: Current vaccination policies are not sufficient to achieve and maintain measles elimination in most countries. Strategies targeting unvaccinated children before they enter primary school can remarkably enhance the fulfilment of WHO targets.

The Inverse Method for a Childhood Infectious Disease Model with Its Application to Pre-vaccination and Post-vaccination Measles Data.

In this paper, we improve the classic SEIR model by separating the juvenile group and the adult group to better describe the dynamics of childhood infectious diseases. We perform stability analysis to study the asymptotic dynamics of the new model, and perform sensitivity analysis to uncover the relative importance of the parameters on infection. The transmission rate is a key parameter in controlling the spread of an infectious disease as it directly determines the disease incidence. However, it is essentially impossible to measure the transmission rate for certain infectious diseases. We introduce an inverse method for our new model, which can extract the time-dependent transmission rate from either prevalence data or incidence data in existing open databases. Pre- and post-vaccination measles data sets from Liverpool and London are applied to estimate the time-varying transmission rate. From the Fourier transform of the transmission rate of Liverpool and London, we observe two spectral peaks with frequencies 1/year and 3/year. These dominant frequencies are robust with respect to different initial values. The dominant 1/year frequency is consistent with common belief that measles is driven by seasonal factors such as environmental changes and immune system changes and the 3/year frequency indicates the superiority of school contacts in driving measles transmission over other seasonal factors. Our results show that in coastal cities, the main modulator of the transmission of measles virus, paramyxovirus, is school seasons. On the other hand, in landlocked cities, both weather and school seasons have almost the same influence on paramyxovirus transmission.

Measles vaccine potency and sero-conversion rates among infants receiving measles immunization in Ilorin, Kwara State, Nigeria.

This study was designed to assess the seroconversion rate of measles vaccine among infants receiving measles immunization in Ilorin, Nigeria. The pre- and post-measles vaccination sera of the children were tested using the Haemagglutination Inhibition test. The measles vaccines administered at the immunization centre were also tested for their potency using in-vitro titration method. Only 286 (71.5%) of the vacinees returned to give post-vaccination samples. All the infants screened had low pre-vaccination measles antibody titers. Thirty one (8.0%) of the infants had measles prior to vaccination. The seroconversion pattern showed that 196 (68.6%) of the infants developed protective antibody titers. Low seroconversion rate reported in this study was due to low vaccine potency. The titers of vaccines with low potency ranged between log10(-1.0)-log10(-2.25) TCID/per dose. This was beside other non specific antiviral substances exhibited virus neutralizing activity. Only 3 (50%) of the 6 vaccine vials tested had virus titers of log10(-3.25) to log10(-3.5), which fell above the cut-off point recommended by the World Health Organization for measles vaccines. The sero-conversion rate of 68.6% observed among vaccinees is far lower than the immunity level of 95% required stopping measles transmission in an endemic community. Failure of 31.4% of these infants to sero-convert post vaccination can be attributed partly to administration of sub-potent vaccines. There is need for improvement and maintenance of effective vaccine cold chain system in Nigeria. There is need also for periodic monitoring of post-vaccination antibody titers as well as vaccine potency status in order to ensure development of protective seroconversion rates.

MEASLES IN VACCINATED CHILDREN 1.5 TO 3 YEARS OF AGE IN RURAL COMMUNITY OF DISTRICT PESHAWAR, PAKISTAN.

BACKGROUND: In many developing countries measles is a leading cause of childhood morbidity and mortality. Despite of vaccination thousands of children have been infected by measles virus during last couple of years in Pakistan. The objective of this study was to determine the measles vaccination coverage rate and frequency of measles among vaccinated children of age 1.5-3 years in rural community of district Peshawar. METHODS: The cross-sectional study was carried out among 385 children aged 1.5-3 year of rural community of Peshawar. After taking informed consent from parents/guardians a predesigned questionnaire was filled. Evidence of vaccination and measles history was taken by vaccination card, doctor prescription and parent/guardian recall. Data was gathered and analysed by using SPSS-16. RESULTS: Of the 385 children, 361 (93.7%) were vaccinated against measles at 9 month. It was found that 27 (7.48%) vaccinated children had measles history of which 23 (6.74%) were infected after 9 month vaccination. One hundred and ninety-two (49.8%) children were vaccinated both at 9 and 15 months, and 14 (7.29%) dual vaccinated children had a measles history, 9 among them (4.68%) were infected after taking both measles doses. CONCLUSION: The occurrence of measles among vaccinated children and low coverage rate of second dose of measles vaccine raises many questions about vaccination program and its efficacy. Further studies are needed to evaluate the influence of other predisposing factors like vaccine quality, manufacturer, supply, cold chain, handling, nutritional status of children and technical approach, on measles vaccine efficacy.

Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies.

The inhibition of vaccination by maternal antibodies is a widely observed phenomenon in human and veterinary medicine. Maternal antibodies are known to suppress the B-cell response. This is similar to antibody feedback mechanism studies where passively transferred antibody inhibits the B-cell response against particulate antigens because of epitope masking. In the absence of experimental data addressing the mechanism underlying inhibition by maternal antibodies, it has been suggested that epitope masking explains the inhibition by maternal antibodies, too. Here we report that in the cotton rat model of measles virus (MV) vaccination passively transferred MV-specific immunoglobulin G inhibit B-cell responses through cross-linking of the B-cell receptor with FcγRIIB. The extent of inhibition increases with the number of antibodies engaging FcγRIIB and depends on the Fc region of antibody and its isotype. This inhibition can be partially overcome by injection of MV-specific monoclonal IgM antibody. IgM stimulates the B-cell directly through cross-linking the B-cell receptor via complement protein 3d and antigen to the complement receptor 2 signaling complex. These data demonstrate that maternal antibodies inhibit B-cell responses by interaction with the inhibitory/regulatory FcγRIIB receptor and not through epitope masking.

Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations? An analysis of surveillance data from Navrongo, Ghana.

OBJECTIVES: Studies from low-income countries have suggested that routine vaccinations may have non-specific effects on child mortality; measles vaccine (MV) is associated with lower mortality and diphtheria-tetanus-pertussis (DTP) with relatively higher mortality. We used data from Navrongo, Ghana, to examine the impact of vaccinations on child mortality. METHODS: Vaccination status was assessed at the initiation of a trial of vitamin A supplementation and after 12 and 24 months of follow-up. Within the placebo group, we compared the mortality over the first 4 months and the full 2 years of follow-up for different vaccination status groups with different likelihoods of additional vaccinations during follow-up. The frequency of additional vaccinations was assessed among children whose vaccination card was seen at 12 and 24 months of follow-up. RESULTS: Among children with a vaccination card, more than 75% received missing DTP or MV during the first 12 months of follow-up, whereas only 25% received these vaccines among children with no vaccination card at enrollment. Children without a card at enrollment had a significant threefold higher mortality over the 2-year follow-up period than those fully vaccinated. The small group of children with DTP3-4 but no MV at enrollment had lower mortality than children without a card and had the same mortality as fully vaccinated children. In contrast, children with 1-2 DTP doses but no MV had a higher mortality during the first 4 months than children without a card [MRR = 1.65 (0.95, 2.87)]; compared with the fully vaccinated children, they had significantly higher mortality after 4 months [MRR = 2.38 (1.07, 5.30)] and after 2 years [MRR = 2.41 (1.41, 4.15)]. Children with 0-2 DTP doses at enrollment had higher mortality after 4 months (MRR = 1.67 (0.82, 3.43) and after 2 years [MRR = 1.85 (1.16, 2.95)] than children who had all three doses of DTP at enrollment. CONCLUSIONS: As hypothesised, DTP vaccination was associated with higher child mortality than measles vaccination. To optimise vaccination policies, routine vaccinations need to be evaluated in randomised trials measuring the impact on survival.

Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.

Measles in Vaccinated People: Epidemiology and Challenges in Surveillance and Diagnosis in the Post-Elimination Phase. Spain, 2014-2020.

The MMR vaccination program was introduced in Spain in 1981. Consistently high vaccination coverage has led to Spain being declared free of endemic measles transmission since 2014. A few imported and import-related cases were reported during the post-elimination phase (2014 to 2020), with very low incidence: three cases per million of inhabitants a year, 70% in adults. In the post-elimination phase an increasing proportion of measles appeared in two-dose vaccinated individuals (up to 14%), posing a challenge to surveillance and laboratory investigations. Severity and clinical presentation were milder among the vaccinated. The IgM response varied and the viral load decreased, making the virus more difficult to detect. A valid set of samples (serum, urine and throat swab) is strongly recommended for accurate case classification. One third of measles in fully vaccinated people was contracted in healthcare settings, mainly in doctors and nurses, consistent with the important role of high intensity exposure in measles breakthrough cases. Surveillance protocols and laboratory algorithms should be adapted in advanced elimination settings. Reinforcing the immunity of people working in high exposure environments, such as healthcare settings, and implementing additional infection control measures, such as masking and social distancing, are becoming crucial for the global aim of measles eradication.

[Measles vaccination: why and how?] / Mazelenvaccinatie: waarom en hoe?

The measles virus is highly contagious and may hit non-immune populations very hard, as observed on remote islands. The first live-attenuated measles virus vaccine was registered in the United States in 1963, and was imported to the Netherlands from 1968 onwards. Production was taken over by the National Institute for Public Health (RIV). Because the burden of disease was still high, measles vaccination was introduced into the Dutch National Immunisation Programme in 1976; since 1987 this has been in the form of the combined measles, mumps and rubella (MMR) vaccination. The MMR vaccine was also initially imported and later manufactured by the National Institute for Public Health and the Environment (RIVM). Since then, measles epidemics have almost exclusively affected unvaccinated populations. Vaccinated individuals are thus well-protected, as are unvaccinated individuals as long as the rate of vaccination in the surrounding population is sufficiently high. Unvaccinated individuals who travel to countries where measles is endemic are still at a higher risk. Recent studies show that measles not only has the classical symptoms, but also damages the immune system.

Starvation-Induced Differential Virotherapy Using an Oncolytic Measles Vaccine Virus.

Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting normal cells against off-target lysis. Human colorectal carcinoma (CRC) cell lines as well as human normal colon cell lines were subjected to various starvation regimes and infected with MeV-GFP. The applied fasting regimes were either short-term (24 h pre-infection) or long-term (24 h pre- plus 96 h post-infection). Cell-killing features of (i) virotherapy, (ii) starvation, as well as (iii) the combination of both were analyzed by cell viability assays and virus growth curves. Remarkably, while long-term low-serum, standard glucose starvation potentiated the efficacy of MeV-mediated cell killing in CRC cells, it was found to be decreased in normal colon cells. Interestingly, viral replication of MeV-GFP in CRC cells was decreased in long-term-starved cells and increased after short-term low-glucose, low-serum starvation. In conclusion, starvation-based virotherapy has the potential to differentially enhance MeV-mediated oncolysis in the context of CRC cancer patients while protecting normal colon cells from unwanted off-target effects.

Ex vivo analysis of cytotoxic T lymphocytes to measles antigens during infection and after vaccination in Gambian children.

The study of cytotoxic T cell responses to measles antigens during infection and after vaccination may provide insight into the immunopathology of the infection. It will also provide a knowledge of the immunity conferred by wild or attenuated virus, which will help in the design of new vaccines. Direct cytotoxic T cell responses, which did not require in vitro restimulation, were measured from peripheral blood by a standard 51Cr-release assay in 35 patients with acute measles, using HLA class I matched allogeneic B cells as targets. 77% showed specific responses to measles fusion protein, 69% to the hemagglutinin, and 50% to the nucleoprotein. These responses, which were related to severity of disease and history of previous vaccination, had waned by 14-24 wk after measles when memory responses to the same antigens could be elicited by restimulation in 71% of the 13 patients tested. A similar pattern followed vaccination: direct cytotoxic responses to fusion and hemagglutinin proteins were shown in 70% of the 20 children tested while 50% responded to the nucleoprotein. These responses, which were mediated by both CD8(+) and CD4(+) cells, faded over 6 wk when memory responses could be restimulated. Thus, a vigorous cytotoxic T lymphocyte response to fusion, hemagglutinin, and nucleoproteins is important in both natural and vaccine-induced immunity to measles.

Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme.

Despite the most aggressive medical and surgical treatments, glioblastoma multiforme remains incurable with a median survival of <1 year. We investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus (MV), derived from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA). CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of glioblastoma cell lines including U87, U118, and U251 at MOIs 0.1, 1, and 10 resulted in significant cytopathic effect consisting of excessive syncycial formation and massive cell death at 72-96 h from infection. terminal deoxynucleotidyltransferase-mediated nick end labeling assays demonstrated the mechanism of cell death to be predominantly apoptotic. The efficacy of this approach in vivo was examined in BALB/c nude mice by using both s.c. and intracranial orthotopic U87 tumor models. In the s.c. U87 model, mice with established xenografts were treated with a total dose of 8 x 10(7) plaque forming units of MV-CEA, administered i.v. Mice treated with UV light inactivated MV, and untreated mice with established U87 tumors were used as controls. There was statistically significant regression of s.c. tumors (P < 0.001) and prolongation of survival (P = 0.007) in MV-CEA treated animals compared with the two control groups. In the intracranial orthotopic U87 model, there was significant regression of intracranial U87 tumors treated with intratumoral administration of MV-CEA at a total dose of 1.8 x 10(6) plaque forming units as assessed by magnetic resonance image (P = 0.002), and statistically significant prolongation of survival as compared with mice that received UV-inactivated virus and untreated mice (P = 0.02). Histological examination of brains of MV-CEA-treated animals revealed complete regression of the tumor with the presence of a residual glial scar and reactive changes, mainly presence of hemosiderin-laden macrophages. In addition, CEA levels in the peripheral blood in both the s.c. and orthotopic models increased before tumor regression, indicating viral gene expression, and returned to normal when the tumors regressed. Ifnar(ko) CD46 Ge transgenic mice, susceptible to MV infection, were used to assess central nervous system toxicity of MV-CEA. Intracranial administration of MV-CEA into the caudate nucleus of Ifnar(ko) CD46 Ge did not result in clinical neurotoxicity. Pathologic examination demonstrated limited microglial infiltration surrounding the injection site. In summary, MV-CEA has potent antitumor activity against gliomas in vitro, as well as in both s.c. and orthotopic U87 animal models. Monitoring CEA levels in the serum can serve as a low-risk method of detecting viral gene expression during treatment, and could allow dose optimization and individualization of treatment.

Novel epi-virotherapeutic treatment of pancreatic cancer combining the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus.

Oncolytic viruses (OV) constitute highly promising innovative biological anticancer agents. However, like every other antitumoral compound, OV are also faced with both primary and secondary mechanisms of resistance. To overcome those barriers and moreover amplify the therapeutic potential of OV, we evaluated a novel combined approach composed of the oral histone deacetylase inhibitor resminostat and an oncolytic measles vaccine virus (MeV) for a future epi­virotherapy of pancreatic ductal adenocarcinoma. Cytotoxicity assays revealed that combined epi-virotherapeutic treatment of four well-characterized human pancreatic cancer cell lines resulted in a beneficial tumor cell killing as compared to either monotherapeutic approach. Notably, epi-virotherapeutic treatment of MIA PaCa-2 and partly also of PANC­1 pancreatic cancer cells resulted in a tumor cell mass reduction being significantly more pronounced than it would be expected in case of an additive effect only, indicating a synergistic mode of action when combining resminostat with MeV. We further found that the epigenetic compound resminostat neither impaired MeV growth kinetics nor prevented the activation of the interferon signaling pathway which plays an important role in mediating primary and secondary resistances to OV. Moreover, we yielded information that the pharma-codynamic function of resminostat was presumably not altered in the course of pancreatic cancer cell infections with MeV. Taken together, these promising results favor the onset of epi-viro-thera-peutic clinical trials in patients suffering from advanced pancreatic ductal adenocarcinoma.

T cell immunity to measles viral proteins in infants and adults after measles immunization.

Vaccination of infants against measles remains of global importance, and proposed new vaccine strategies include the use of measles proteins or synthetic peptides as immunogens. We studied cell-mediated immunity to whole measles antigen and measles proteins in immune adults and infants after measles vaccine. Further, we measured CD8+ T cell responses to peptide pools corresponding to the nucelocapsid (N) measles protein in adults given measles vaccine. Cell-mediated immune responses to three of four measles proteins were equivalent to those against whole measles antigen in immune adults. Responses to the fusion (F) protein were lower in infants compared to whole measles antigen (p < or = 0.03). Infant responses to both whole measles antigen and the F protein were lower compared with these responses in adults (p < or = 0.001). CD8+ T cell responses to N peptide pools varied, and differed between immune HLA-A2-positive individuals compared with naive and HLA-A2-negative subjects after measles vaccination. The measles-specific T cell adaptive response of infants is limited compared to adults, including responses to the F protein.

Prior infection by respiratory syncytial virus or parainfluenza viruses augments virus-specific IgG responses induced by the measles/mumps/rubella vaccine.

We found previously that immunizing cyclophosphamide-treated mice with one Paramyxoviridae virus mixed with dimethyl dioctadecyl ammonium bromide induces T cells which apparently also recognize other Paramyxoviridae viruses. This finding and the fact that respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) infect children early in life led us to ask if prior RSV or PIV infections influence the antibody response to measles and mumps vaccine viruses. Detection of virus-specific IgG in serum specimens collected randomly or at defined times after measles/mumps/rubella (MMR) vaccination was done with solid-phase enzyme immunoassays. The antibody-binding data obtained were converted to serum antibody titers by an immunoassay curve-fitting computer program. Prior infection by RSV and PIVs correlated with an augmented IgG response not only to measles and mumps virus, but also to rubella virus. Furthermore, the augmentation was greater for responders below the median response. These data show that common early childhood viral infections can influence immunity induced by the MMR vaccine.

Dynamical complexity in age-structured models of the transmission of the measles virus: epidemiological implications at high levels of vaccine uptake.

This article explores the effect of increasingly finely stratified age structure on the dynamical properties of deterministic metapopulation models of the transmission of the measles virus. The dynamical simplicity of earlier age-structured models is shown to break down once the age-specific force of infection is no longer assumed to be constant across all child age classes below 5 years of age. While the biennial epidemics characteristic of earlier models are still observed, additional higher period stable cycles arise and coexist with the biennial cycle. The existence of multiple stable limit cycles necessarily implies model sensitivity on initial conditions, and for certain parameter values, chaotic dynamics are observed. Using a novel parameterization of the magnitude of seasonal forcing we are also able to make more biologically relevant comparisons between the dynamics of age- and non-age-structured models than have hitherto been possible. The epidemiological significance of these results is discussed, and we demonstrate that perturbations of the kind produced by intensive vaccination programs can shift transmission dynamics between biennial and triennial cycles. The possible implications of this work for studies of intermittency and infection persistence are also considered.

[Effect of infectious factors on human and animal cytogenetic structures]. / Vliianie infektsionnykh faktorov na tsitogeneticheskie struktury cheloveka i zhivotnykh

The analysis of blood leucocyte chromosomes has been carried out on 60 patients with different infectious diseases (influenza, measles, scarlet fever, and disentery), and on 47 patients immunized against measles, tick-born encephalitis, typhoid fever and brucellosis. The mutagenic influence of viruses on the genital cells of mice and on the human somatic cells in vitro was studied. Both viruses and bacteria appeared to be able to bring about different breaks in human and animal cells.

[Effect of viral vaccines on animal bone marrow cell chromosomes]. / Issledovanie vliianiia protivovirusnykh vaktsin na khromosomy kletok kostnogo mozga zhivotnykh

A comparative study on the effect of a number of viral vaccines (live and inactivated vaccinia, poliovirus type II, measles, rabies vaccines) on chromosomes of mouse bone marrow cells was carried out. Most vaccines were found to impair the process of first divisions of these cells after vaccination. Live vaccinia vaccine and live fixed rabies virus cause an increase in the rate of structural chromosome aberrations at later intervals, 30-90 days after immunization. The main type of chromosome disorders is chromatid break. Some of the live vaccines studied (poliovaccine type II, measles vaccine) and inactivated vaccines caused no increase in the rate of cromosome structure disorders as compared to the control. Live fixed rabies virus exerts a stronger impairing effect on division of mouse bone marrow cells than a rabies vaccine with residual virulence. A rabies vaccine completely inactivated by UV-irradiation had no impairing effect on chromosomes of immunized animals. Thus, some live vaccines, unlike inactivated ones, cause chromosome disorders in bone marrow cells of mice late after immunization and, apparently, subsequent death of some cells with the most important distrubances.

[Effect of a live measles vaccine on the chromosome apparatus of mouse bone marrow cells]. / Vliianie zhivoi protivokorevoi vaktsiny na khromosomnyi apparat kletok kostnogo mozga myshei.

Vaccination of albino mice with live measles vaccine caused an increase in the chromosome aberrations frequency during the period from the 30th till the 120th day of the experiment. The maximum increase in the number of chromosome aberrations as well as in centromeric and telomeric chromosome associations was observed 60 days after immunization. Chromatid breaks were main type of the structural aberrations observed.

[Study of the chromosomes in the bone marrow cells of mice inoculated subsequently with various vaccines]. / Issledovanie khromosom v kletkakh kostnogo kozga myshei, privitykh posledovatel'no razlichnymi vaktsinami

Studies in the effect of a complex of inoculating preparations (poliovaccine, APDD-vaccine, smallpox vaccine, measles vaccine) on dividing cells of bone marrow in mice in line CC57Br showed that a reduction of the interval between introduction of vaccines different in the antigenic respect from 14 days to 4 days results in an increase in frequency of structural chromosomal aberrations 1-2 months after the whole course of inoculations.