Saccharide dosage content of meningococcal polysaccharide conjugate vaccines determined using WHO International Standards for serogroup A, C, W, Y and X polysaccharides.

Potency of meningococcal polysaccharide-protein conjugate vaccines relies on the polysaccharide content to prevent meningitis. NIBSC, as the official national control laboratory in UK, analysed ten different mono- and multi-meningococcal conjugate vaccines, using established International Standards for meningococcal serogroups A, C, W, Y and X, by resorcinol or HPAEC-PAD assay. Most saccharide contents were within ±20% of their claimed content for licensure with taking different O-acetylation levels into consideration, with only MenC content in two vaccines below (by 60% and 54%) the labelled value, however, previous study showed different dosage was not necessarily correlated to the immunogenicity of those vaccines. This study demonstrated the use of International Standards to quantify saccharide content in polysaccharide-based vaccines with different percentage of O-acetylation. These International Standards are suitable to serve as either quantitative standard or calibrator of in-house standards, with supplied stability data.

Routine Childhood Vaccines Given From 1 through 18 Years of Age.

In addition to the vaccines due in the first year of life, the US Advisory Committee on Immunization Practices recommends that children continue to receive vaccines regularly against a variety of infectious diseases. Starting at 12 to 15 months of life, these include the two-dose measles-mumps-rubella vaccine series and the two-dose varicella vaccine series. Also in the second year of life, infants should begin the two-dose hepatitis A vaccine series and complete the Haemophilus influenzae type B vaccine series as well as the pneumococcal conjugate vaccine series. Before 19 months of life, infants should receive the third dose of the poliovirus vaccine and the fourth dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The final doses of poliovirus and tetanus-diphtheria-acellular pertussis vaccines are both due at 4 to 6 years of life. Before each influenza season, every child should receive the influenza vaccine. Those less than 9 years of age who previously received less than two doses need two doses a month apart. At 11 to 12 years of life, all should get two doses of the human papillomavirus vaccine, the adolescent/adult version of the tetanus-diphtheria-acellular pertussis vaccine, and begin a two-dose series of meningococcal ACWY vaccine. Each of these vaccines is due when the vaccine works to protect against both an immediate risk as well as to provide long-term protection. Each vaccine-preventable disease varies in terms of the nature of exposure, the form of the morbidity, the risk of mortality, and potential to prevent or ameliorate its harm.

Recurrent meningococcal meningitis with complement 6 (C6) deficiency: A case report.

RATIONALE: Late complement deficiency increases susceptibility to meningococcal disease and recurrent infections. In Korea, 5 case reports have described meningococcal disease with complement deficiency. However, C6 deficiency has not been described previously. PATIENT CONCERNS: A 21-year-old police trainee presented with recurrent meningococcal meningitis. He was housed in communal living quarters until 20 days before the initial symptom onset. DIAGNOSIS: He was diagnosed with meningococcal meningitis with C6 deficiency. INTERVENTIONS: He was treated with intravenous ceftriaxone. An additional dose of quadrivalent meningococcal conjugate vaccine was administered after discharge. OUTCOMES: He was discharged without complications. LESSONS: Screening for complement deficiency is necessary in patients with a history of recurrent meningococcal infections to provide appropriate care and prevent recurrent infections.

Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases.

Eculizumab, a humanized monoclonal antibody to complement C5, is a therapeutic drug for atypical hemolytic-uremic syndrome (aHUS) that inhibits the terminal pathway of complement. Patients on eculizumab therapy may become more susceptible to infection with capsule-forming bacteria, including meningococci. Therefore, meningococcal vaccination is required for patients who are on eculizumab therapy. However, the means to prevent meningococcal infection in infants who cannot be vaccinated with the available meningococcal vaccine have not yet been established internationally. In two infants with aHUS at 4-5 months after birth, prophylactic oral amoxicillin was administered, and meningococcal infection was not detected during the period between the initiation of eculizumab therapy and the administration of meningococcal vaccine. Neither adverse events related to amoxicillin nor thrombotic microangiopathy occurred during the treatment. Thus, oral administration of amoxicillin may be effective for preventing meningococcal infection under treatment with eculizumab in infants who have not received meningococcal vaccination.

Meningococcal and pneumococcal carriage in Hajj pilgrims: findings of a randomized controlled trial.

BACKGROUND: Intense congestion during the Hajj pilgrimage amplifies the risk of meningococcal carriage and disease, and there have been many meningococcal outbreaks reported amongst pilgrims. Thus, a strict vaccination policy is enforced by the host country and either polysaccharide or conjugate quadrivalent meningococcal vaccines are mandatory. However, unlike conjugate vaccines, the polysaccharide vaccine is not thought to reduce pharyngeal carriage of meningococci. METHODS: A single-blinded, randomized, controlled trial amongst pilgrims from Saudi Arabia and Australia during the Hajj seasons of 2016-2017 was conducted to compare MenACWY-Conjugate vaccine with MenACWY-Polysaccharide vaccine, to determine if the conjugate vaccine is more effective in reducing asymptomatic carriage of meningococci, and whether the effect may be long-standing. Oropharyngeal swabs were obtained pre-, immediately post- and 6-11 months following completion of Hajj and tested for the presence of meningococci. RESULTS: Amongst 2000 individuals approached, only 1146 participants aged 18-91 (mean 37.6) years agreed to participate and were randomized to receive either the polysaccharide (n = 561) or the conjugate (n = 561) vaccine, 60.8% were male, and 93.5% were from Saudi Arabia. Amongst oropharyngeal swabs obtained before Hajj, only two (0.2%) tested positive for Neisseria meningitidis. Similarly, meningococci were identified in only one sample at each of the post-Hajj and late follow-up visits. None of the carriage isolates were amongst the serogroups covered by the vaccines. A post hoc analysis of the third swabs revealed that 22.4% of all participants (50/223) were positive for Streptococcus pneumoniae nucleic acid. CONCLUSION: The low overall carriage rate of meningococci found amongst Hajj pilgrims in 2016 and 2017 demonstrates a successful vaccination policy, but neither supports nor refutes the superiority of meningococcal conjugate ACWY vaccine over the polysaccharide vaccine against carriage. Although an association could not be established in this study, molecular epidemiology would help to establish the role of Hajj in facilitating transmission of pneumococci and inform vaccination policy.

Control Strategy Approach for a Well-Characterized Vaccine Drug Product.

Trumenba (MenB-FHbp; bivalent rLP2086), the first meningococcal serogroup B vaccine approved in the United States and subsequently approved in Europe, Canada, and Australia, is well-characterized. Pfizer devised a control strategy approach by using a simplified control strategy wheel for Trumenba based on International Council for Harmonisation (ICH) Q8 (R2), Q9, Q10, and Q11 guidelines, which provide complementary guidance on pharmaceutical development, quality risk management, quality systems, and development and manufacture of drug substances, respectively. These guidelines ensure product quality using a scientific and risk-based approach. Trumenba contains two factor H binding proteins (FHbps), one from each of the two FHbp subfamilies (A and B), adsorbed onto aluminum phosphate. Trumenba manufacturing processes are complicated by the recombinant protein expression of Subfamily A and B proteins and the nature of the drug product (suspension in syringes); the latter also introduces challenges in controlling product critical quality attributes during the development process. In such complex systems, the control strategy is critical to ensuring consistent desired product quality; it also supports the regulatory requirement of continued improvement through continuous process verification and aids regulatory filing. This article describes Pfizer's approach toward robust control strategy development, built on product and process understanding, and links control strategy to regulatory document sections and flow of controls. Specifically, an approach is presented on product quality attribute criticality determination based on safety and efficacy and on an understanding of process parameter criticality. This was achieved by studying the impact of the approach on product quality attributes to define process parameter and in-process controls. This approach is further explained through Trumenba case studies, highlighting specific quality attributes and the associated controls implemented, and provides a holistic view of controls employed for both drug substance and drug product.

The Hajj 2019 Vaccine Requirements and Possible New Challenges.

Each year millions of pilgrims perform the annual Hajj from more than 180 countries around the world. This is one of the largest mass gathering events and may result in the occurrence and spread of infectious diseases. As such, there are mandatory vaccinations for the pilgrims such as meningococcal vaccines. The 2019 annual Hajj will take place during August 8-13, 2019. Thus, we review the recommended and mandated vaccinations for the 2019 Hajj and Umrah. The mandatory vaccines required to secure the visa include the quadrivalent meningococcal vaccine for all pilgrims, while yellow fever, and poliomyelitis vaccines are required for pilgrims coming from countries endemic or with disease activity. The recommended vaccines are influenza, pneumococcal, in addition to full compliance with basic vaccines for all pilgrims against diphtheria, tetanus, pertussis, polio, measles, and mumps. It is imperative to continue surveillance for the spread of antimicrobial resistance and occurrence of all infectious diseases causing outbreaks across the globe in the last year, like Zika virus, MDR-Typhoid, Nipah, Ebola, cholera, chikungunya and Middle East Respiratory Syndrome Coronavirus.

Monoclonal Antibodies Against the Capsular Polysaccharides A, C, Y, W, and X of Neisseria meningitidis: A Platform for the Quality Control of Meningococcal Vaccines.

Vaccination has reduced morbidity and mortality of many diseases that previously caused devastating epidemics and deaths globally. Vaccines as a biological product may contain microorganisms or their derivatives. This aspect together with the fact that they are administered to healthy individuals (mainly children) means that approximately 70% of vaccines development time is dedicated to quality control. Monoclonal antibodies (MAbs) have become essential analytical tools for application in ELISAs, Western and Dot blotting, immunoprecipitation, and flow cytometric assays that ensure the quality control of vaccines. The aim of this work is to present a review of the methods used to obtain a platform of MAbs against Neisseria meningitidis polysaccharide antigens to use as an analytical tool for quality control of anti-meningococcal polysaccharide (Ps) vaccines. The MAbs obtained are used in five sandwich ELISAs developed for Ps quantification. The assays showed good reproducibility and repeatability, with quantitation and detection limits below 1 ng/mL. Dot Blot, as the Identity test of the Ps vaccine, was carried out to positively identify licensed and experimental vaccines. All assays described are suitable for the screening of multiple vaccine samples and could be useful for monitoring lot-to-lot consistency and stability.

Mass chemoprophylaxis for control of outbreaks of meningococcal disease.

Although vaccination is the main strategy used to control meningococcal disease outbreaks, mass chemoprophylaxis has also been used as an immediate response to outbreaks, either to supplement vaccination or when vaccination is not possible. However, public health guidelines regarding the use of mass chemoprophylaxis for outbreak control vary by country, partly because the impact of mass chemoprophylaxis on the course of an individual outbreak is difficult to assess. We have reviewed data for the use of mass chemoprophylaxis during 33 outbreaks that occurred both in military populations and in communities and non-military organisations. In most outbreaks, no additional cases of meningococcal disease occurred after mass chemoprophylaxis, or cases occurred only in individuals who had not received prophylaxis. A delay of several weeks was common before cases occurred among prophylaxis recipients. Overall, the outbreak reports that we reviewed suggest that mass chemoprophylaxis might provide temporary protection to chemoprophylaxis recipients during outbreaks.

Evaluation of candidate international standards for meningococcal serogroups A and X polysaccharide.

Polysaccharide (PS) based meningococcal vaccines are primarily evaluated by physicochemical methods to ensure batches are consistently manufactured. As PS content is determined by different methods across numerous laboratories, there is a need for International Standards (IS) to calibrate the assays. Following the successful introduction of the WHO Meningococcal group C (MenC) IS in 2011, NIBSC initiated projects to prepare similar standards for groups A, W, Y and X (MenA/W/Y/X) to standardise all meningococcal- PS based vaccines. On the basis of results from a collaborative study to evaluate preparations of MenA and MenX PS, both were established by the WHO Expert Committee on Biological Standardization in Oct 2015 as; the First WHO International Standard for the Meningococcal Group A polysaccharide with a content of 0.845 ± 0.043 mg MenA PS per ampoule (expanded uncertainty with coverage factor of k=2.45 corresponding to a 95% level of confidence); the First WHO International Standard for the Meningococcal Group X polysaccharide with a content of 0.776 ± 0.089 mg MenX PS per ampoule (expanded uncertainty with coverage factor of k=2.45), as determined by quantitative NMR. The standards are available from NIBSC, who act as guardians and distributors of the material under the auspices of WHO.

10 Practice Recommendations in Adult Vaccination Administration.

Although the provision of immunoprophylaxis to children has become routine in the practice of pediatric preventive care, the same is not true in adult primary care. Contributing to this problem is a lack of knowledge among providers of adult preventive care. This review aimed to bolster providers' understanding of adult vaccinations by highlighting changes in vaccination recommendations and addressing common knowledge gaps. This is not a comprehensive list of vaccination recommendations, but rather the "top 10" common misconceptions, advancements, and updates we have found in our reading of the vaccination literature and in our own experience in a training institution.

Regulatory Pathways That Facilitated Timely Registration of a New Group A Meningococcal Conjugate Vaccine for Africa's Meningitis Belt Countries.

BACKGROUND: Through its normative and public health leadership roles, the World Health Organization (WHO) plays a key role in the availability of vaccine products in low-and middle-income countries. The recent introduction of a new group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), in Africa exemplifies this process. WHO requires that any new vaccine to be introduced in countries for public health reasons and supplied through United Nations centralized mechanisms be licensed by the national regulatory agency (NRA) in the producing country, then prequalified and given a marketing authorization in the user countries. METHODS: PsA-TT was manufactured by the Serum Institute of India, Ltd (SIIL), which submitted a license application in April 2009 to the Drug Controller General of India (DCGI), the Indian NRA responsible for licensing vaccines. WHO encouraged the DCGI to establish a collaboration with Health Canada's Centre for Vaccine Evaluation for the review. Through this collaborative effort, registration was facilitated and in December 2009 an export license was granted to SIIL, which subsequently submitted an application for WHO prequalification. RESULTS: Given the importance of the vaccine, WHO "fast tracked" the prequalification review, and after a detailed review and site visit, WHO prequalification was granted to PsA-TT in June 2010. Country use of the new vaccine could not occur until the vaccine was a registered product in each country seeking its use. WHO facilitated country reviews by conducting regulatory training exercises (in French and English) for country NRA staff, which used the PsA-TT registration as a case study. CONCLUSIONS: PsA-TT was gradually registered in African countries as vaccine introduction proceeded. The regulatory pathway for this new group A meningococcal conjugate vaccine proved to be a useful training opportunity both in India and Africa, because the availability of the vaccine was a high African public health priority, as well as for WHO as a case study to facilitate registration of vaccines based on reliance on other regulatory bodies.

Brazilian meningococcal C conjugate vaccine: Scaling up studies.

Several outbreaks caused by Neisseria meningitidis group C have been occurred in different regions of Brazil. A conjugate vaccine for Neisseria meningitidis was produced by chemical linkage between periodate-oxidized meningococcal C polysaccharide and hydrazide-activated monomeric tetanus toxoid via a modified reductive amination conjugation method. Vaccine safety and immunogenicity tested in Phase I and II trials showed satisfactory results. Before starting Phase III trials, vaccine production was scaled up to obtain industrial lots under Good Manufacture Practices (GMP). Comparative analysis between data obtained from industrial and pilot scales of the meningococcal C conjugate bulk showed similar execution times in the scaling up production process without significant losses or alterations in the quality attributes of purified compounds. In conclusion, scale up was considered satisfactory and the Brazilian meningococcal conjugate vaccine production aiming to perform Phase III trials is feasible.

Efetividade da vacina conjugada contra o meningococo C em menores de dois anos / Effectiveness of conjugate vaccine against meningococcus C in under two years

Objetivo: Estimar o impacto da vacina conjugada contra o meningococo C (VCMC), na incidência e mortalidade, nas coortes de nascidos com e sem indicação de vacinação, no município de São Paulo (MSP); e estimar a efetividade direta da VCMC segundo esquema do Programa Nacional de Imunização. Métodos: O impacto foi avaliado por estudo descritivo, abrangendo casos de doença meningocócica (DM) notificados ao MSP, de 1998 a 2012. A definição de caso é a adotada pelo Ministério da Saúde. Descreveu-se o comportamento da DM no MSP para todo período e analisou-se a tendência da incidência e mortalidade da DM global e por faixa etária de 2008 a 2012, utilizando o modelo de Poisson. O impacto da VCMC foi analisado por meio das razões de taxas de incidência e mortalidade nos períodos anterior e posterior a introdução da VCMC. Estimou-se a fração prevenida na população (FPP) para mensurar o impacto, comparando-se taxas de incidência e mortalidade globais da DM, por faixa etária e sorogrupo C, de 2012 com as de 2009. Para estimativa da efetividade da VCMC utilizou-se estudo de caso-controle de base populacional, com quatro controles para cada caso, pareado pela área de residência dos casos. Casos e controles foram selecionados entre nascidos a partir de janeiro/2009. Casos eram aqueles com DM pelo sorogrupo C confirmado por cultura e/ou reação em cadeia de polimerase em tempo real, de 2011 a 2013, internados em hospitais do MSP, notificados à vigilância do município. Controles foram selecionados entre crianças residentes na vizinhança dos casos, sem história de DM. A efetividade da vacina foi estimada pela fórmula (1-odds ratio para vacinação). As odds ratios (OR) não ajustadas e ajustadas e respectivos intervalos de confiança (IC95 por cento ) foram estimados por regressão 11 logística condicional múltipla. A associação entre ser vacinado com VCMC e a variável dependente, DM pelo sorogrupo C, foi mensurada pela estimativa da OR após ajuste para potenciais confundidores. Resultados: O impacto da VCMC na incidência da DM por todos os sorogrupos, mensurado pela FPP foi de 62,7 por cento , 69,6 por cento e 61,4 por cento para, respectivamente menores um, um e dois anos; na DM pelo sorogrupo C de 81,6 por cento e 67,9 por cento para menores de dois anos e de dois a três anos. Houve impacto na taxa de mortalidade global da DM medido pela FPP de 86,2 por cento e 77,8 por cento respectivamente para menores de dois anos e de dois a três anos e na mortalidade da DM pelo sorogrupo C a FPP foi de 84,2 por cento para menores de quatro anos. A efetividade da VCMC foi de 97,7 por cento (IC95 por cento :99,6 por cento -89,6 por cento ) ajustada para idade, número de pessoas no quarto da criança e renda familiar. Conclusões: A estratégia brasileira com a VCMC resultou em elevado impacto nas coortes de nascidos com indicação de vacinação, mais acentuado nas taxas de mortalidade, sugerindo que a vacina confere não só proteção para a doença, mas também para formas mais graves. A VCMC foi altamente efetiva na faixa etária alvo.

Objective: To assess the impact of meningococcal C conjugate vaccine (MCCV), to estimate incidence and mortality rates of meningococcal disease (MD) in birth cohorts recommended and not recommended for vaccination and to measure direct vaccine effectiveness of the National Vaccination Program immunization schedule. Methods: We assessed the impact of MCCV in a descriptive study including cases of MD reported in the city of Sao Paulo, Brazil, from 1998 to 2012. We used the standard case definition recommended by the Brazilian Ministry of Health for MD reporting. We assessed changes in the disease epidemiology in the city for the entire study period and estimated incidence and mortality rates of MD (overall and by age group) from 2008 to 2012 using Poisson regression models. We conducted an impact analysis of MCCV by comparing incidence and mortality rates of MD before and after vaccine introduction. We also estimated the population prevented fraction (PPF) by comparing incidence and mortality rates of MD between 2009 and 2012 in the entire population and by age group and serogroup C. To measure vaccine effectiveness, we carried out a population-based case-control study matched for area of residence with a 4-to-1 ratio of controls to cases. Cases and controls were selected among children born from January 2009. Cases were those children admitted to the citys hospitals who were diagnosed with MD serogroup C (MDC) confirmed by culture and/or real-time polymerase chain reaction and reported to the surveillance system from 2011 to 2013. Controls were selected among children with no history of MD from neighboring areas of cases. We calculated vaccine effectiveness using the formula (1 odds ratio [OR] for 13 vaccination) and estimated crude and adjusted ORs and related 95 per cent confidence intervals (95 per cent CI) by conditional multiple logistic regression. We assessed the association between MCCV vaccination and MDC the dependent variable by estimating OR after adjustment for the potential confounders. Results: There was an impact of MCCV on the incidence of MD in all serogroups, the PPF among children under age one, age one, and age two were 62.7 per cent , 69.6 per cent , and 61.4 per cent , respectively; and in serogroup C, the PPF in children under age two and age two to three were 81.6 per cent and 67.9 per cent . There was also an impact on the overall mortality rate of MD, the PPF in children under age two and age two to three were 86.2 per cent and 77.8 per cent ; and on mortality of MDC, the PPF was 84.2 per cent in children under age four. MCCV effectiveness in children was 97.7 per cent (95 per cent CI 99.6 per cent 89.6 per cent ) after adjusting for age, number of persons per room, and household income. Conclusions: The MCCV strategy implemented in Brazil had a high impact on birth cohorts recommended for vaccination. This impact was more pronounced on mortality rates, which suggests that, in addition to preventing disease, MCCV can prevent more severe forms of MD. MCCV proved highly effective in the age groups targeted.

Quantitation of serogroups in multivalent polysaccharide-based meningococcal vaccines: optimisation of hydrolysis conditions and chromatographic methods.

Quantitative determination of the individual polysaccharide components in multivalent meningococcal vaccines is an important step in manufacturing and regulatory control. Current methods are complicated due to the use of multiple chromatographic setups and/or other analytical techniques for the four meningococcal serogroup polysaccharides (A, C, Y, W135). In addition, different methods are sometimes used depending on whether or not the polysaccharide is conjugated to a carrier protein. In an effort to simplify such analyses, hydrolysis conditions were determined for the optimal yield of each characteristic saccharide from the respective repeating units. One condition was identified for mannosamine-6-phosphate from MenA, one for neuraminic acid from MenC, and one for both glucose and galactose from MenY and MenW135, respectively. These conditions, initially assessed for monovalent solutions, were then confirmed for a quadrivalent solution. The monosaccharide products were separated, identified and quantitated using a single HPAEC-PAD protocol, with a customised multi-stage linear gradient eluent profile and one column setup, for determination of all four serogroup components. Comparison to calibration curves constructed from sets of monosaccharide or hydrolysed polysaccharide standards allowed for the quantitation of each characteristic serogroup monosaccharide in polysaccharide and polysaccharide-conjugate vaccines. When required, molecular size separation using a non-cellulosic centrifugal filter device effectively removed all interfering saccharide excipient without loss of serogroup polysaccharides. These methods were used to analyse multiple lots of a number of different monovalent or multivalent real polysaccharide-based vaccine products, in liquid or lyophilised powder formulations, with or without excipients. The methods were demonstrated to be highly reproducible and very useful for the evaluation of antigen content and lot-to-lot consistency of manufacture. The methods described here represent an increase in precision, level of accuracy and efficiency compared to current methods, and may be adaptable for evaluation of other types of polysaccharide-based vaccines.

Improved production process for native outer membrane vesicle vaccine against Neisseria meningitidis.

An improved detergent-free process has been developed to produce vaccine based on native outer membrane vesicles (NOMV) against Neisseria meningitidis serogroup B. Performance was evaluated with the NonaMen vaccine concept, which provides broad coverage based on nine distinct PorA antigens. Scalable aseptic equipment was implemented, replacing undesirable steps like ultracentrifugation, inactivation with phenol, and the use of preservatives. The resulting process is more consistent and gives a higher yield than published reference processes, enabling NOMV production at commercial scale. Product quality met preliminary specifications for 9 consecutive batches, and an ongoing study confirmed real-time stability up to 12 months after production. As the NOMV had low endotoxic activity and induced high bactericidal titres in mice, they are expected to be safe and effective in humans. The production process is not limited to NonaMen and may be applicable for other N. meningitidis serogroups and other gram-negative pathogens. The current results therefore facilitate the late-stage development and clinical evaluation of NOMV vaccines.