Auswahl der wissenschaftlichen Literatur zum Thema „Measles virus, vaccine, humoral immune response, cellular immune response“

Abstract Measles is a leading cause of vaccine-preventable mortality worldwide. To facilitate vaccine distribution, aerosol immunization has been proposed, but the immune response induced, and protection afforded, by live attenuated measles virus (MV) vaccine (LAV) given by the respiratory route have not been systematically studied. Rhesus macaques were immunized with liquid or powder LAV through a nebulizer, an endotracheal tube, or parenterally by intramuscular injection. The method of immunization significantly influenced the induction of the humoral and cellular immune responses to LAV, but the effect on the cellular immune response was not correlated with the effect on the humoral response. For instance, nebulizer immunization induced good T cell, but poor antibody responses. Intratracheal challenge with wild type MV showed that respiratory immunization did not fully prevent infection. However, animals primed with nebulizer LAV showed accelerated viral clearance from both blood and respiratory tract that coincided with faster and higher levels of MV-specific recall CD4+/CD8+ T-cell responses compared to controls. Therefore, the route of immunization influences the induction of humoral, cellular and protective immune responses to measles vaccine. Protection correlates with neutralizing antibody and not with T-cell responses. Although, memory T cells alone are not sufficient for preventing MV infection, a robust recall T cell response does accelerate viral clearance.

ABSTRACT The protective effect of measles immunization is due to humoral and cell-mediated immune responses. Little is known about cell-mediated immunity (CMI) to measles vaccine virus, the relative contribution of CD4+ and CD8+ T cells to variability in such immune responses, and the immunologic longevity of the CMI after measles vaccination in humans. Our study characterizes cellular immune response in subjects seronegative or highly seropositive for measles vaccine immunoglobulin G-specific antibody, aged 15 to 25 years, previously immunized with two doses of measles-mumps-rubella II vaccine. We evaluated the ability of subjects to respond to measles vaccine virus by measuring measles virus-specific T-cell proliferation. We examined the frequencies of measles virus-specific memory Th1 and Th2 cells by an ELISPOT assay. Our results demonstrated that proliferation of T cells in seronegative subjects was significantly lower than that for highly seropositive subjects (P = 0.003). Gamma interferon (IFN-γ) secretion predominated over interleukin 4 (IL-4) secretion in response to measles virus in both groups. The median frequency of measles virus-reactive CD8+ T cells secreting IFN-γ was 0.09% in seronegative subjects and 0.43% in highly seropositive subjects (P = 0.04). The median frequency of CD4+ T cells secreting IL-4 in response to measles virus was 0.03% in seronegative subjects and 0.09% in highly seropositive subjects (P = 0.005). These data confirm the presence of measles virus-specific cellular immune responses post-measles vaccine immunization in humans. The detection of measles virus-induced IFN-γ and IL-4 production by ELISPOT can be used to identify measles virus-specific low-frequency memory T cells in subjects immunized with measles vaccine. These differences agree in directionality with the observed antibody response phenotype.

Despite adherence to the policy of mass measles vaccination in the majority of countries, this infection still remains far from being fully eradicated. Measles outbreaks are reported worldwide, when the vast majority of cases are recorded in subjects of 18—35 years of age. Studies on assessing measles IgG antibody level in different regions of Russia reveal increased percentage of measles seronegative subjects among young adults. Current study was aimed at investigating formation of humoral and cellular immunity after measles vaccination in seronegative adults aged 18 to 30 years old. There were enrolled 50 measles seronegative healthy volunteers aged 18 to 30 years old. Level of anti-measles IgM and IgG antibodies was measured by ELISA (Vector-Best, Russia). Subclasses of measles specific IgG antibodies were analyzed by ELISA, by replacing IgG conjugate for IgG1, IgG2, IgG3, IgG4 conjugates, whereas measles specific IgA antibodies were estimated by ELISA with IgA conjugate (Polygnost, Russia) at a concentration of 1 μg/ml. Antibody avidity was assessed by ELISA (Euroimmun, Germany). Cell-mediated measles immunity was estimated by CD107a surface expression on CD8hi T cell subset stimulated by measles virus-derived antigens. A specific cellular response to measles antigens before vaccination was detected in 50% of examined subjects, whereas 40% samples showed no signs of cellular immune response, with 10% of remaining cases described as equivocal. It was found that 6 weeks after vaccination all vaccinated subjects developed measles specific IgG antibodies at protective level reaching 1.33 (0.85—1.82) IU/ml [Me (LQ—UQ)]. Anti-measles IgA antibodies were of 0.655 (0.423—1.208) IU/ml [Me (LQ—UQ)]. However, no measles specific IgM antibodies were detected 6 weeks after vaccination. In addition, primary type of immune response (dominant low-avidity anti-measles antibodies IgG3 subclass) to measles vaccination was observed in 24 out of 50 subjects, whereas 26 subjects developed secondary type of immune response (high-avidity anti-measles antibodies dominated by IgG1 subclass). A measles specific cellular immune response was observed in 47 of the 50 examined subjects, and in 3 volunteers it was equivocal. Further analysis revealed a cohort of subjects who were not vaccinated against measles (18 subjects), although 60% of them provided medical record on previous dual measles vaccination occurred in childhood. Another cohort consisted of subjects who had medical record of measles vaccination in childhood (32 subjects), but lost protective measles antibodies produced by plasma cells (23 subjects), and memory T cells (3 subjects), or measles antibodies and memory B cells (6 subjects) over time. Such pattern evidences that measles-specific cellular and humoral arms immune responses were developed and maintained independently of each other.

Various strategies for dealing with COVID-19 have been carried out since the WHO declared COVID-19 as an international health emergency. One of the preventive strategies is the development of vaccines. Various vaccines have been developed worldwide. As of April 13, 2021, there were 184 vaccine candidates in the pre-clinical phase and 16 vaccine candidates currently in phase III clinical trials using several platforms, such as inactivated viruses, vector viruses, and protein subunits, and mRNA. Clinical trials of the SARS-CoV-2 vaccine include a screening test consisting of thorough physical examination and laboratory tests. The safety of clinical trials is evaluated based on laboratory test results referring to the standard toxicity grading scale. Immunogenicity assessment at the stage of clinical trials of vaccines includes assessment of humoral and cellular immunogenicity. The humoral immunogenicity test measures the ability of antibodies to neutralize the virus with the live virus neutralization test, Pseudo Virus Neutralization Test (pVNT), and Surrogate Virus Neutralization Test (sVNT) method. The cellular immunogenicity response aims to assess the immune response that leads to the Th1-cell phenotype. The COVID-19 vaccine under development is expected to trigger a helper 1 (Th1) cell response. Th1-producing Interferon-g (IFNg) is formed during acute viral infection, and Th1-type immune response correlates with milder disease. This is one of the considerations in vaccination. Th1-cell phenotype as part of cellular immunogenicity can be evaluated with ELISPOT, interferon-gamma release assay, and flow cytometry using blood samples that have been cultured with the administration of specific SARS-CoV-2 peptides. This literature review aims to study various immunogenicity assessments in the laboratory for clinical trials of COVID-19 vaccines.

With the implementation of the WHO strategic plan for the elimination of measles, the number of measles cases in European Region has decreased. However, outbreaks are still observed. Although most measles cases affect unvaccinated individuals, cases with vaccinated persons are also reported. Furthermore, it was described that a high percentage of young people in Poland exhibit no presence of anti-MeV IgG despite the high level of vaccination covering no less than 97% of the Polish population. Strong evidence exists that immunity to measles is complex and depends on both the humoral and cellular response and although antibodies have been used as correlates of immunity, it is increasingly being considered that antibody-based definitions of vaccine success or failure may be incomplete. Here, we investigated immunity to measles as the reactivity of CD4 T cells to stimulation with vaccine as well as wild strains of measles virus (MeV) isolated in Poland, in young vaccinated persons and subjects infected naturally. Evidence for the presence of MeV-specific memory cells years after infection or vaccination was found, however the cells ofvaccinees and naturally infected subjects reacted differently in contact with wild and vaccine MeV strains. Furthermore, the presence of a significant proportion of non-responder vaccinees was observed. In conclusion, our results may have implications for studies on the monitoring of the complexity of post-vaccine immune response.

Congenital cytomegalovirus infection (cCMV) may affect about 1% of all newborns all over the world as a result of either a primary or recurrent human cytomegalovirus (HCMV) infection. While about 90% of infants affected by cCMV are asymptomatic at birth, the remaining 10% are symptomatic often with neurodevelopmental impairment and sensorineural hearing loss. In view of identifying the best approach to vaccine prevention of cCMV, this review will examine the most important steps made in the study of the immune response to, and diagnosis of, HCMV infection. The maternal immune response and immune correlates of protection are being partially identified with a partial contribution given by our laboratory. The diagnosis of primary infection is often difficult to achieve in the first three months of pregnancy, which is the time primarily involved in virus transmission to the fetus in association with the most severe symptoms and sequelae. Prevention of cCMV is anticipated by prevention of primary infection in early pregnancy by means of different measures, such as (i) behavioral-educational measures, (ii) immunoglobulin administration, (iii) antiviral treatment with valaciclovir. However, the most promising approach to cCMV prevention appears to be the development of a non-living vaccine, including at least three viral antigens: gB, pentamer complex gHgLpUL128L, and pp65, which have been shown to be able to stimulate both the humoral and the cellular arms of the maternal immune response. Primary HCMV infection may be managed in pregnancy by counseling of the couples involved by a team of specialists that includes virologists, obstetricians, infectivologists and neonatologists.

Despite the high efficacy of the BNT162b2 vaccine in the general population, data on its immunogenicity among frail elderly individuals are limited. Recently, levels of anti-SARS-CoV-2 spike IgG antibodies and serum neutralization titers were confirmed as good immune markers of protection against the virus, with evidence showing a reverse correlation between these two parameters and susceptibility to infection. Here we analyzed sera from 138 nursing home residents (median age of 88.9 years) and 312 nursing home staff (median age of 50.7 years) to determine the humoral response to two doses of the BNT162b2 vaccine, and found markedly decreased serum anti-spike antibody levels and neutralization titers in the nursing home resident (NHR) group, with over 11% non-responders compared to only 1.3% among the controls. Moreover, three months post-vaccination, a significant decrease in antibody titers was observed in COVID-19-naive nursing home residents. Subsequent flow cytometry and interferon gamma secretion analyses indicated that antibody non-responders among NHRs also failed to mount cellular responses. The presented data emphasize that additional measures are needed in the population of frail elderly individuals. Given the high proportion of non-responders among NHRs, continued monitoring should be considered in this group.

ABSTRACT Toxicity is a major factor limiting the development and use of potent adjuvants for human mucosally delivered vaccines. Novel adjuvant formulations have recently become available, and in the present study two have been used for intranasal immunization with a synthetic peptide immunogen (MAP-M2). This peptide represents a multiple antigenic peptide containing multiple copies of a mimotope M2, a peptide mimic of a conformational epitope of the fusion protein of measles virus. MAP-M2 was administered intranasally to experimental animals together with synthetic oligodeoxynucleotides containing unmethylated CpG motifs with or without a mutant of wild-type enterotoxin of Escherichia coli (LTR72). The combination of the mutant toxin LTR72 and the CpG repeats, codelivered with a peptide immunogen, induced both local and systemic peptide- and pathogen-specific humoral and cellular immune responses comparable to those obtained after intranasal immunization with the wild-type toxin LT. In addition, this combination of adjuvants induced a predominantly immunoglobulin G2a antibody response. If both the LTR72 and CpG adjuvants are shown to be safe for use in humans, this particular combination would appear to have potential as an adjuvant for mucosally delivered vaccines in humans.

The coronavirus are a wide group of viruses among that the SARS-CoV-2 is included (family Coronaviridae, subfamily Coronavirinae, genus Betacoronavirus and subgenus Sarbecovirus). Its main structural proteins are the membrane (M), the envelope (E), the nucleocapsid (N) and spike (S). The immune response to SARS-CoV-2 involves the cellular and the humoral sides, with neutralizing antibodies fundamentally directed against the S antigen. Although the seroprevalence data are frequently assumed as protection markers, no necessarily they are. In Spain, it is estimated that, to assure the herd immunity, at least four-fifths of the population should be immunoprotected. Due the high fatality rate of COVID-19, the acquisition of the protection only by the natural infection it not assumable and other measures as the mass immunization are required. Currently, there are several vaccine prototypes (including life virus, viral vectors, peptides and proteins and nucleic acid) in different phase of clinical evaluation. Foreseeably, some of these news vaccines would be soon commercially available. In this text, aspects related to these issues are reviewed.

BACKGROUND: Unprecedented anti-epidemic measures and the widespread use of vaccines against COVID-19 have reduced the rate of hospitalization and mortality from the disease, but have not stopped the SARS-CoV-2 pandemic spread. The development of live vaccines against COVID-19, capable of providing the formation of a long-term humoral and cellular immune response and cross-protection against new SARS-CoV-2 variants of concern, is relevant. Previously at the I.I. Mechnikov Research Institute of Vaccines and Sera SARS-CoV-2 cold-adapted (ca, cold-adapted) variants were obtained. This work is aimed to search for methodological approaches that allow in vitro screening studies to assess the attenuation (att) phenotype of ca SARS-CoV-2 variants. MATERIALS AND METHODS: The SARS-CoV-2 laboratory strain Dubrovka and its variants were cultured in Vero and Calu-3 cells. Quantitation of the virus was carried out by titration in Vero cells and by real-time RT-PCR. The attenuation (att) phenotype of SARS-CoV-2 variants was determined on an animal model of COVID-19 on Syrian hamsters. RESULTS: In experiments on Syrian hamsters, the presence of the att phenotype in the ca variants of the virus was established. Animals infected with virus ca variants had significantly less weight lost, had less viral load in the lungs and brain and less pronounced pathological changes in the lungs compared to infection with the virulent strain. In vitro experiments on Vero and Calu-3 cells revealed probable attenuation markers of the virus ca variants for syrian hamsters: (1) ability to reproduce at low temperature (ca phenotype); (2) inability to reproduce at 39 C (ts phenotype); (3) changes in the species and tissue specificity of the virus. CONCLUSIONS: The developed methodological approaches to the identification of SARS-CoV-2 attenuation markers are a valuable tool for monitoring the stability of the phenotype of candidate vaccine strains.

Measles virus belongs to the Morbillivirus genus, Paramixoviridae family. It is the causative agent of a highly contagious acute infective disease, typical of infancy, characterized by fever, skin rash, cough and conjunctivitis, and a generalized immune suppression (Griffin, 2013). The virus is transmitted through the respiratory tract, multiplicates in its upper part and in regional lymph nodes, thus resulting in lymphatic and hematic dissemination with appearance of first clinical signs after 9-19 days (de Vries et al., 2015). In 30% of the cases, complications in the lower respiratory tract or the central nervous system (CNS) can occur. The first sign of infection is represented by an early immune depression, due to the loss of B and T immune memory cells (Mina et al., 2015), resulting in an increased susceptibility to opportunistic infections and to life-threatening complications such as pneumonia and/or gastro-intestinal disease (de Vries et al., 2015). However, this type of disease is paradoxically associated with the induction of a strong and specific immune response to the virus, which is usually permanent (Laksono et al., 2016). There is no specific treatment against measles, and this is the reason why vaccination is considered the best strategy against the virus. Furthermore, the monotypic nature of the virus and the lack of an animal reservoir, make measles a considerable candidate for eradication (Rota et al., 2016). Although a combined vaccine, called MMR (measles, mumps and rubella) is used in routinely vaccination schedule, measles remains a significative cause of morbidity and mortality, particularly during infancy (Moss & Griffin, 2012; Wolfson et al., 2009; Nandy et al., 2003). MMR live attenuated vaccine is very efficacious in protecting people against measles, mumps, and rubella, and preventing the complications caused by these diseases. The measles virus contained in the vaccine is represented by the live attenuated Edmoston B strain. The World Health Organization recommends two doses of vaccine for all children and adults; the first dose should be given at 13-15 months of age. The second dose is often done at 5 - 6 years, in Italy. About 3 out of 100 people who get two doses of MMR vaccine will get measles if exposed to the virus. However, they are more likely to have a milder illness, and are also less likely to spread the disease to other people (Centers for Disease Control and Prevention, 2018). Epidemiologic studies have shown that the level of neutralizing antibodies at the time of exposure to wild type (WT) virus in the community is a good indicator of protection from infection, with higher titers necessary to prevent infection than to prevent disease (rash) (Chen et al., 1990). High avidity antibodies are required to neutralize CD150-mediated WT MeV infection of lymphoid cells (Polack et al., 2003). However, levels of circulating anti-measles neutralizing antibody tend to reduce or even to fade during lifetime, especially among vaccinated subjects (Kennedy et al., 2019; Davidkin et al., 2008; Carryn et al., 2019; Seagle et al., 2018; Gonçalves et al., 2015; Le Baron et al., 2007). Because CD4+ T cell help is required for isotype and affinity maturation of antibody-secreting cells, B cell memory and maturation of CD8+ T cell memory, cellular immune response is also important for the induction of protective immunity (Laksono et al., 2018). All these things highlight the necessity to invest on studies focused on the correlates of protection against Measles virus. Recent evaluation systems for vaccines point towards the measurement of Tcell quality with regards to cytokine secretion as a protective correlate in addition to antibody titers in serum during the course of an immune response. Although the generation of immune memory supports the concept of vaccine efficacy, direct assessment of immune memory cells and their precursors has not yet been established as a correlate of protection. With the growing knowledge on the phenotype, function and localization of the immune memory cells in the body, researchers think that these cells may provide a novel correlate of protection for evaluation of more efficacious vaccines. Finally, transcriptome-level characterization (mRNA-Seq data) of responses to measles virus stimulation in antibody responders (either vaccinated or naturally infected) and those who have not responded to the vaccine, could help to identify plausible regulators (genes/pathways) that drive the observed differences among these subjects. Such study may help to develop a panel of biomarkers to monitor, besides the antibody response, the immune response to measles vaccine with the aim to protect, in case of outbreaks, not only the fragile subjects, but also the vaccinated subjects who eventually become seronegative along the time, with a booster composed of specific, immunogenic MeV proteins.