Changing dynamics of invasive meningococcal disease in the UK following the introduction of the novel 4CMenB vaccine

The epidemiology of infectious diseases must consider a number of aspects of the disease along with its control and prevention, as these will ultimately alter disease incidence, trends and distribution within a population. For many infectious diseases, the greatest medical tool available to combat them is vaccination. Historically, the UK has successfully controlled invasive meningococcal disease through vaccination. As a result, the majority of disease seen in today’s epidemiological landscape is caused by a previously non-preventable form. Monitoring the epidemiology of invasive meningococcal disease relies on strong surveillance systems which in turn, allow for the evaluation of vaccination programmes. An understanding of the relationship between a vaccination programme and its effect on the epidemiology of the targeted disease is vital for assessing the success of a programme and gives insight into how these programmes may be improved. This thesis presents eight studies, presented in three sections, that used epidemiological data to demonstrate the success of the national infant MenB vaccination programme in England. The studies presented have provided baseline estimates of the burden of invasive meningococcal disease (IMD) and the predicted strain coverage of the 4CMenB vaccine against circulating strains in England prior to the vaccine’s national introduction in September 2015. These studies also provided the first ever estimates of 4CMenB’s vaccine effectiveness at a reduced vaccination schedule, to that used for licensure, along with the impact on MenB disease in the group with the highest incidence of disease, children under the age of five, who were targeted with the vaccine. Further, these studies looked at the epidemiology and trends of disease in vulnerable populations in England, highlighting the markedly increased risk in a young person on long term complement inhibitor therapy and raising awareness of the increased risk in cases who initially present with a less common presentation and its implications for the public health and clinical management of these cases. Finally, these studies explored cases of IMD in pregnant women in England over a four-year period and showed that while disease during pregnancy can be severe, there was an unusual 1 finding of a significantly decreased risk of IMD in pregnant women compared to nonpregnant women of a similar age. The combined findings of these studies show the success of the first nationally funded 4CMenB immunisation programme and its subsequent effects on the epidemiology of invasive meningococcal disease in England

Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak?

The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines

The everchanging epidemiology of meningococcal disease worldwide and the potential for prevention through vaccination.

Neisseria meningitidis is a major cause of bacterial meningitis and septicaemia worldwide and is associated with high case fatality rates and serious life-long complications among survivors. Twelve serogroups are recognised, of which six (A, B, C, W, X and Y) are responsible for nearly all cases of invasive meningococcal disease (IMD). The incidence of IMD and responsible serogroups vary widely both geographically and over time. For the first time, effective vaccines against all these serogroups are available or nearing licensure. Over the past two decades, IMD incidence has been declining across most parts of the world through a combination of successful meningococcal immunisation programmes and secular trends. The introduction of meningococcal C conjugate vaccines in the early 2000s was associated with rapid declines in meningococcal C disease, whilst implementation of a meningococcal A conjugate vaccine across the African meningitis belt led to near-elimination of meningococcal A disease. Consequently, other serogroups have become more important causes of IMD. In particular, the emergence of a hypervirulent meningococcal group W clone has led many countries to shift from monovalent meningococcal C to quadrivalent ACWY conjugate vaccines in their national immunisation programmes. Additionally, the recent licensure of two protein-based, broad-spectrum meningococcal B vaccines finally provides protection against the most common group responsible for childhood IMD across Europe and Australia. This review describes global IMD epidemiology across each continent and trends over time, the serogroups responsible for IMD, the impact of meningococcal immunisation programmes and future needs to eliminate this devastating disease

Primary meningococcal conjunctivitis: Summary of evidence for the clinical and public health management of cases and close contacts.

BACKGROUND: Neisseria meningitidis is a rare cause of acute bacterial conjunctivitis but can progress to invasive meningococcal disease (IMD) in the case and their close contacts. There is, however, a lack of consensus on the clinical and public health management of primary meningococcal conjunctivitis (PMC). METHODS: We searched Ovid MEDLINE via PubMed, EMBASE and NHS evidence (up to June 2019) for all publications relating to meningococcal conjunctivitis to provide an evidence-base for developing guidelines for the management of PMC cases and their close contacts. RESULTS: The review identified a 10-29% risk of IMD among PMC cases within two days of onset of eye infection (range: 3 h to 4 days). In one study, the risk of IMD in PMC cases treated with systemic antibiotics was 19 times lower than topical antibiotics alone (p = 0.001). IMD among close contacts of PMC cases is uncommon but potentially fatal. Whether meningococcal vaccination for PMC cases or close contacts provides any additional benefit is unclear. CONCLUSIONS: Systemic antibiotic treatment significantly reduces the risk of invasive disease in PMC cases, while antibiotic chemoprophylaxis for close contacts will reduce their risk of secondary IMD. These findings need to be highlighted in relevant clinical and public health guidelines

WHO Global Situational Alert System: a mixed methods multistage approach to identify country-level COVID-19 alerts

Background Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched.Methods The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of ‘High’ or above were added to an operational watchlist and assistance was deployed as needed.Results Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%–67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available.Conclusions The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators