Reports

Advances in Paediatric Immunization: Targeting the Last Remaining Serogroup Towards Complete Meningococcal Disease Control
Improving Responses to First-line Treatment in Chronic Myeloid Leukemia

Extended Protection Against Serious Infections: Meningococcal B Disease and Influenza

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 29th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID)

The Hague, The Netherlands / June 7-11, 2011

Medical Editor: Dr. Julie Frère, Montreal, Québec

Whether it manifests as sepsis or meningitis, invasive meningococcal disease (IMD) is well known to physicians who treat children. Recognizing the infection before it becomes fulminant is challenging, however, as the prodrome is non-specific and therefore difficult to reliably distinguish between much larger numbers of children who have self-limiting viral illnesses. If it is IMD, the child rapidly decompensates and the illness continues to progress even after initiation of appropriate antibiotic therapy.

In some Canadian provinces, including Québec, a 1-dose MenC vaccination program given to infants at 12 months of age has been in place since 2002 and vaccination coverage by the age of 24 months is approximately 90%. As reported here by epidemiologist Dr. Rodica Gilca, Institut national de santé publique du Québec, Québec City, between 1997 and 2010, approximately 900 IMD cases have been identified across the province. “Serogroup B has been the most prevalent serogroup among IMD cases, with the exception of year 2001-2002, when there was an epidemic of serogroup C disease,” she noted.

Indeed, in the last 3 years, 97% of all IMD in Québec residents aged 0 to 19 years was caused by serogroup B disease, she added, indicating that serogroup C disease now accounts for <5% of all IMD in the province. The proportion of serogroup C disease was identical for children <5 as well, where again, in the last 3 years, 97% of IMD in this age group was due to serogroup B. In fact, only 1 case of IMD in young children was not due to serogroup B disease and that 1 case was not due to serogroup C disease (Figure 1).

As Dr. Gilca also noted, the overall incidence of serogroup B disease in adolescents was relatively low until about 2003-2004. “Since then, we have seen a very rapid increase, starting in 2004, where serogroup B disease has increased sixfold in adolescents between 15 and 19 years of age compared to previous periods,” she reported. This is in contrast to serogroup B disease in children <5 years, where the incidence of serogroup B disease has remained relatively constant over the years. “Serogroup B is responsible for the vast majority of IMD in the province of Québec,” Dr. Gilca stated, “and I think overall most of the cases of IMD we see in Canada today are also due to serogroup B disease.”

Figure 1.


Quadrivalent Vaccines

As discussed here at ESPID by Dr. Marco Safadi, Assistant Professor of Pediatrics, Faculdade e Ciências Médicas Santa Casa de São Paulo, Brazil, the unpredictable epidemiology of meningococcal disease underscores the need for vaccines that provide comprehensive coverage against all serogroups. In reviewing results from a large phase III study in infants, the MenACWY-CRM (Menveo) quadrivalent vaccine was shown to be highly immunogenic and well tolerated. One month after the first 3 doses, over 90% of infants achieved human serum bactericidal antibody (hSBA) titres =1:8 which correlate with seroprotection. Antibody levels did drop significantly prior to the booster dose. However, 1 month following the booster dose of MenACWY-CRM, between 95 and 100% of infants achieved protective antibody titres against the 4 serogroups.

Importantly as well, recent evidence indicates that physicians can successfully boost seroprotective responses using the same quadrivalent vaccine in infants who have previously received the MenC conjugate vaccine. “Studies including >20,000 subjects in various countries have shown that the MenACWY-CRM vaccine was immunogenic and well tolerated in infants, toddlers, adolescents and adults,” Dr. Safadi reported, “and this provides us with a real possibility of broad protection against meningococcal disease in all age groups.”

Serogroup B Disease

Until now, broad protection against meningococcal disease did not extend to serogroup B disease which causes the lion’s share of IMD. Data from the UK showed the peak of serogroup B disease is at 5 months, as noted by infectious disease/vaccine researcher Dr. Peter Dull, San Francisco, California. “You really do want early protection,” he confirmed. In Canada, a 2009 statement from the National Advisory Committee on Immunization (NACI) reported that rates of serogroup B disease are “particularly high” in infants and children <4 years of age, but disease can occur at any age (CCDR 2009;36:ACS-3). In fact, in 2006, serogroup B caused 82% of all IMD in infants under the age of 1 year and 72% of all IMD in children 1 to 4; in adolescents between the ages of 15 and 19, serogroup B caused 68% of all IMD.

That early protection has now been demonstrated for a novel vaccine against serogroup B, the four component meningococcal B (4CMenB) vaccine. Developed by vaccine researcher Rino Rappuoli, PhD, Siena, Italy, researchers used a process called reverse vaccinology to identify multiple surface-exposed antigens that are important to the survival, fitness or virulence of the organism. This multi-component structure provides both synergistic bactericidal activity and limits the emergence of mutant escape variants, as Dr. Dull explained. An outer membrane vesicle (OMV) component from a New Zealand outbreak strain was added to provide additional immunogenicity.

To date, over 1500 adolescents and adults have been enrolled in the 4CMenB clinical trial program, as have almost 5000 infants starting from the age of 2 months. A wide range of primary vaccination schedules have been explored in an effort to work the vaccine into various infant vaccination schedules. In evaluating the immunogenicity of the 4CMenB vaccine, researchers were required to quantify response to each of the 4 components of the vaccine: factor H-binding protein variant 1 (fHbp); Neisserial adhesin A (NadA); Neisserial heparin-binding antigen (NHBA); and PorA 1.4 (the OMV component). Given at 2, 4 and 6 months of age, 100%, 100%, 84% and 84% of approximately 3600 infants who received the primary series had achieved seroprotective bactericidal titres =1:5 to fHbp, NadA, PorA 1.4 and NHBA, respectively. “Importantly,” Dr. Dull added, “we saw similar responses in both groups of infants who received the 4CMenB vaccine with or without routine infant vaccinations.”

The vaccine is reactogenic and causes fever in about 30% of infants. However, the fever follows a very consistent pattern: it peaks at about 6 hours’ post-vaccination, declines significantly by day 2 and dissipates by day 3. “When parents and physicians are aware of the potential for fever and have a discussion about it, there should be no increase in medically attended fever rates because this did not happen in the open-label portion of the study.” Dr. Dull told ESPID delegates.

Another study by Prymula et al. (ESPID 2011; Abstract P770) also found that high fever was rare when prophylactic acetaminophen was given prior to 4CMenB vaccination, with 1 dose (10-15 mg/kg) given before the vaccine and 2 further doses at intervals of 4-6 hours post-vaccination. Prophylactic acetaminophen did not interfere with the immunogenicity of the vaccine nor with the immunogenicity of routine vaccines given concomitantly.

Prof. Timo Vesikari, University of Tampere Medical School, Finland, also presented responses to a booster dose of the 4CMenB vaccine given at 12 months in infants who had been primed at 2, 4 and 6 months of age. “At 12 months of age, many children still had high levels of hSBA against fHbp and NadA antigens, although hSBA levels were lower against NHBA and OMV antigens,” Prof. Vesikari told delegates. One month after the booster dose, 94 to 100% of children who received the 4CMenB vaccine concomitantly with the measles-mumps-rubella-varicella (MMRV) vaccine as well as those who received the booster dose alone had hSBA titres =1:5 against the 4 antigens. Again, responses to the 4CMenB vaccine were not affected by concomitant MMRV vaccination. “The need for a meningococcal serogroup B vaccine is greatest of all serogroups,” Prof. Vesikari confirmed.

The vaccine has also been tested in adolescents between 11 and 17 years of age, with 92 to 97% of vaccinees achieving bactericidal levels for the 3 antigens contained in the vaccine at that time 1 month after 1 dose; 99 to 100% achieved bactericidal levels after 2 doses. Interestingly, fever was less of an issue in these older recipients and local reactions were largely mild to moderate.

Adjuvanted vs. Inactivated Influenza Vaccines

As discussed by Prof. Fred Zepp, Johannes Gutenberg University, Mainz, Germany, influenza is responsible for >60% of all respiratory disease in the young, with an attack rate of up to 20% in children <4 years of age (Figure 2). Some 40% of influenza-related deaths occur in children <2 years old where the risk of influenza transmission is the highest. “In the first 2 years of life, infants have an untrained and slowly reactive immune system, especially the dendritic cell that takes a much higher signal to become activated and develop a protective immune response,” Prof. Zepp explained.

Consequently, infants in the first few years of life are highly susceptible to influenza infection, he added. Moreover, young children spread the virus both within their own age group and to the community at large, especially to the elderly. When young children get influenza, they are more likely to develop infection-related complications, and hospitalization rates are higher in children under the age of 4 t
roup.

Figure 2.

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Starting at 6 months of age, Ontario introduced a universal influenza vaccination program that covers children up to the age of 4 years. Already, there has been about a 50% reduction in mortality, hospitalization and emergency room use which “very nicely underlines the benefit of a universal vaccination program,” Prof. Zepp observed. This is all the more extraordinary, given that conventional trivalent influenza vaccines (TIVs) are less than 60% effective in recipients <16 years of age; in children <2 years, TIV effectiveness is similar to that of placebo.

Prof. Vesikari described to delegates his involvement in the evaluation of a novel seasonal influenza vaccine, the MF59 adjuvanted vaccine, which has been evaluated in some 2000 infants. Children were between the ages of 6 and 72 months and had to be influenza vaccine-naive. The trial was carried out over 2 influenza seasons. As the first season provided only limited data, results are largely based on findings from the 2008-2009 influenza season. Infants were assigned to either the MF59 adjuvanted vaccine or a conventional TIV vaccine. All children received 2 doses of the assigned vaccine at 28-day intervals, with follow-up through the influenza season over 6 months. Children under 36 months of age received half a dose of the vaccine while older children received a full dose—“so younger children received half a dose of the flu antigens and half a dose of the adjuvant,” Prof. Vesikari noted. Trial end point was laboratory (PCR) confirmed influenza.

In children between the ages of 6 and 72 months, the absolute efficacy of the MF59 vaccine was 89% against vaccine-like strains vs. 45% for the TIV vaccine. Separating out younger from older infants, the absolute efficacy of the MF59 vaccine was 86% for 6- to 36-month-olds vs. 41% for the conventional vaccine. For children between 36 and 72 months of age, the absolute efficacy of the MF59 vaccine was even higher at 96% vs. 48% for the conventional vaccine. When all circulating influenza strains were included in the efficacy analysis, “results do not change much; we have very similar efficacy rates for the MF59 adjuvanted vaccine while the conventional flu vaccine was barely significant,” Prof. Vesikari reported. He added, “In this trial of children between 6 and 72 months, the adjuvanted vaccine was 75% more efficacious than the TIV against influenza caused by all circulating strains regardless of vaccine match, and the high levels of antibody responses seen with the adjuvanted vaccine are sustained throughout the influenza season.”

As reported in an ESPID poster presentation, Arora et al. compared the safety profile of the MF59 adjuvanted vaccine to that of a non-adjuvanted influenza vaccine. In a pooled analysis of 4840 children, approximately half of whom received the MF59 vaccine and the other half a non-adjuvanted comparator, slightly increased local and systemic reactions were observed in the former group. For the youngest children (36 months of age), the most frequently reported local reaction was erythema followed by tenderness. For the older age groups (3 to 9 and 9 to 18), the most frequent local reaction was injection-site pain followed by erythema. Most reactions were mild to moderate and self-limiting, as the authors noted, and adverse events leading to premature withdrawal were similar between the 2 groups.

Also here at ESPID, a separate analysis of the safety of the MF59 adjuvanted vaccine in 6- to =24-month-olds by Tsai et al. showed that in this young age group, 40% of infants receiving the adjuvanted vaccine experienced a local reaction vs. 31% the TIV vaccine, while 55% in both groups had a systemic reaction. The most common local reactions in both groups were mostly mild and transient erythema and injection-site tenderness and the most common systemic reactions were irritability, unusual crying and sleepiness; <1% of infants in either group developed fever =40° C.

Summary

IMD and influenza are important infections in paediatric practice. Vaccines to prevent the majority of IMD that occurs today in Canada, as well as influenza among the very young, are well along in development and approval of both vaccines is anticipated. Once they are available, both the 4CMenB and the MF59 adjuvanted seasonal influenza vaccines will represent a significant advance in the protection of young children and adolescents that extends beyond currently available options.

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