# Modelling the impact of a quadrivalent ACWY meningococcal vaccination and vaccination targeting serogroup B in France

Paolo Bosetti, Laurène Peckeu-Abboud, Roland Michel Andrianasolo, Marc Baguelin, Laure Fonteneau, Ala-Eddine Deghamne, Muhamed-Kheir Taha, Anne-Sophie Barret, Emmanuel Grimprel, Lulla Opatowski, et al.

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Paolo Bosetti, Laurène Peckeu-Abboud, Roland Michel Andrianasolo, Marc Baguelin, Laure Fonteneau, et al. Modelling the impact of a quadrivalent ACWY meningococcal vaccination and vaccination targeting serogroup B in France. Vaccine, 2025, 67, pp.127871. 10.1016/j.vaccine.2025.127871. pasteur-05416928

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# Modelling the impact of a quadrivalent ACWY meningococcal vaccination and vaccination targeting serogroup B in France

Paolo Bosetti<sup>a, *</sup>, Laurène Peckeu-Abboud<sup>b</sup>, Roland Michel Andrianasolo<sup>b</sup>, Marc Baguelin<sup>c,d</sup>, Laure Fonteneau<sup>e</sup>, Ala-Eddine Deghamne<sup>f</sup>, Muhamed-Kheir Taha<sup>f</sup>, Anne-Sophie Barret<sup>e</sup>, Emmanuel Grimprel<sup>g,h</sup>, Lulla Opatowski<sup>i,j</sup>, Daniel Lévy-Bruhl<sup>e</sup>, Simon Cauchemez<sup>a, *</sup>

## ARTICLE INFO

### Keywords:

Neisseria meningitidis
Modelling
Vaccine

## ABSTRACT

Invasive meningococcal disease (IMD) represents a significant global health burden, with high fatality rate and substantial risk of lifelong sequelae. Most cases worldwide are caused by six serogroups (A, B, C, W, X, and Y). Effective vaccines are available to prevent disease caused by serogroups A, B, C, W, and Y. In France, approximately 500 IMD cases occur each year. Since the introduction of mandatory vaccination against serogroup C, the majority of IMD now involve serogroups B, W, and Y. Given these changes in the epidemiology of IMD, French National Authority for Health decided to reconsider its recommendations on meningococcal vaccines.

Using an age structured compartmental model describing meningococcal carriage and IMD cases dynamics of serogroups B, W, and Y, we evaluated the expected impact of introducing vaccination against serogroup ACWY or serogroup B on IMD cases in France. Several scenarios were tested to determine the benefits of vaccination at different ages for both ACWY and serogroup B vaccination, in terms of burden reduction and number of vaccinations needed.

Under our modelling assumptions we find that for ACWY vaccination the optimal strategy is to target infants and adolescents, supplemented by a catch-up campaign up to the age of 25, which could reduce IMD-W cases by 93 % after 20 years. Five to ten years from the start of the vaccination campaign, focusing only on adolescents may achieve similar outcomes, balancing public health benefits while minimizing costs. For serogroup B vaccination, results showed a limited impact, with the overall reduction of IMD-B cases remaining below 20 % in all studied scenarios, even in the long term.

This evaluation informed the discussions of the Technical Vaccination Committee regarding the vaccination strategy for meningococcus and was included in the recommendations of the French National Authority for Health, endorsed by the Ministry of Health.

## 1. Introduction

Invasive meningococcal disease (IMD) represents an important

burden worldwide with high fatality rate and risk of lifelong sequelae. It is caused by *Neisseria meningitidis*, a Gram-negative diplococcus human pathogen that colonises the human upper respiratory tract. This

<footnote><sup>a</sup> Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, Université Paris Cité, INSERM U1332, CNRS UMR2000, Paris, France</footnote>

<footnote><sup>b</sup> Public Health Assessment and Vaccines Assessment Department (SESPEV), Evaluation and Access to Innovation Department (DEAI), Haute Autorité de Santé (HAS), Saint-Denis La Plaine, France</footnote>

<footnote><sup>c</sup> MRC Centre for Global Infectious Disease Analysis and Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health, Imperial College London, London, UK</footnote>

<footnote><sup>d</sup> Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK</footnote>

<footnote><sup>e</sup> Santé publique France, Saint Maurice, France</footnote>

<footnote><sup>f</sup> Invasive bacterial Infections Unit, National Reference Center for Meningococci and Haemophilus influenzae, Institut Pasteur, Université Paris Cité, France</footnote>

<footnote><sup>g</sup> GPIP, Groupe de Pathologie Infectieuse Pédiatrique, Créteil, France</footnote>

<footnote><sup>h</sup> Department of Pediatric, Trousseau Hospital, APHP Paris, France, Sorbonne University, France</footnote>

<footnote><sup>i</sup> Epidemiology and Modelling of Bacterial Escape to Antimicrobials, Institut Pasteur, Paris, France</footnote>

<footnote><sup>j</sup> CESP, Anti-infective evasion and pharmacoepidemiology research team, U1018, INSERM Université Paris-Saclay, UVSQ, France</footnote>

<footnote>* Corresponding authors.
E-mail addresses: paolo.bosetti@pasteur.fr (P. Bosetti), simon.cauchemez@pasteur.fr (S. Cauchemez).</footnote>
bacterium is surrounded by a polysaccharide capsule whose composition defines one of the 12 known serogroups. Six serogroups (A, B, C, W, X and Y) are responsible for almost all IMD cases worldwide. Effective vaccines are available for preventing disease by serogroups A, B, C, W and Y.

In France, approximately 500 cases of IMD are reported annually. Vaccination targeting serogroup C was introduced in France in 2010 as a routine one dose vaccination at 12 months of age complemented with a catch up for all individuals aged between 2 and 24 years. After 2016, an additional dose was included at 5 months of age and in 2018, both doses scheduled before the age of 2 became mandatory and, together with an increased vaccination coverage in older children and adolescents, coincided with a dramatic decrease in IMD cases associated with serogroup C. Accordingly, IMD is currently mainly caused by serogroups B, W and Y, serogroups A and X being not endemic in France. In 2022, vaccination targeting serogroup B became recommended for all infants (with three doses at 3, 5 and 12 months). Vaccination targeting serogroups ACWY and B is also recommended for specific people, for example for individuals at high risk of IMD and their close contacts, as well as for laboratory personnel working with meningococcus.

Important changes in the epidemiology of IMDs have been observed in the last few years. A decline in incidence was observed for all serogroups during 2020–2021 probably because of non-pharmaceutical measures implemented to mitigate the impact of the SARS-CoV-2 pandemic, an effect also observed in several countries and for different bacterial diseases [1]. However, both the impact of the Men-C vaccination, the emergence of hypervirulent W and Y clones and the increase in atypical presentation of IMD in France associated with these serogroups might have led to significant changes in the serogroup distribution [2–5]. Whereas in 2010, the B, C and W-Y serogroups were responsible for respectively 74 %, 17 % and 8 % of notified cases, those proportions changed respectively to 44 %, 1 % and 53 % in 2023 [2]. Although W and Y serogroups were previously described to affect preferentially the elderly and individuals with immunodeficiencies, this sharp increase in serogroups W and Y IMD cases also affected young children (representing 40 % of cases in 2023 in the less than 5 years of age) and adolescents and young adults (42 % of cases were in 15 to 24 years of age) [2]. In light of these evolutions, the French National Authority for Health, the French agency in charge of recommendations on vaccines, was asked by the Ministry of Health to reassess its recommendations on strategies regarding ACWY and B vaccination in infants and adolescents.

Here, we present a deterministic dynamical compartmental model, inspired by previous research [6,7], to assess the impact of potential changes in the meningococcal vaccination program in France, without accounting for interactions between serogroups. Despite advances in research, the epidemiology of meningococcal disease remains poorly understood, particularly the relationship between asymptomatic carriage and invasion. Very few modelling studies have studied the impacts of a men B adolescent vaccination strategy and of a quadrivalent vaccination strategy in the context of the quasi elimination of Menin-gococcal C serogroup and the endemic circulation of hypervirulent W and Y meningococcal strains [2]. Using the model, we evaluated a broad range of scenarios, targeting infants and/or adolescents to assess both the epidemiological impact and the efficiency of different vaccination strategies. Catch-up vaccination scenarios were also evaluated. This analysis informed the discussion of the National Immunization Technical Advisory Group in France and the recommendations of the French National Authority for Health [8], which were endorsed by the Ministry of Health.

## 2. Methods

### 2.1. Model structure

We developed an age-structured compartmental deterministic model to describe the carriage dynamics of serogroups B, C, W, and Y by age group, as well as the dynamics of IMD cases following an approach similar to the one used in Trotter et al. and Beck et al. [6,7]. The French population is divided into 1-year age groups. The same model structure is used independently for each serogroup. Model parameters such as vaccine effectiveness and duration of protection are specified separately for each serogroup.

The compartmental structure of the model is illustrated in Fig. 1. Briefly, individuals of age *i* that are susceptible to meningococcal colonisation are grouped in compartment $S_i$. At each time, they can become carriers at rate $\lambda_i(t)$ and then enter compartment $C_i$. In the absence of vaccination, the force of infection $\lambda_i$ exerted on individuals in age group *i* at time *t* is:

$$\lambda_i(t) = \beta_i \sum_{j} m_{ij} C_j(t) / N_i$$

where *m* is the contact matrix representing the daily contact rate between age groups, $N_i$ is the population size of age group *i*, and $\beta_i$ is the transmissibility associated with age group *i*.

The contact rates by age for France, divided into one-year age bands that characterise the matrix *m*, are taken from Mistry et al. for France [9].

A proportion of individuals $\theta_i(s)$ who become carriers are affected by an IMD (see supplementary information). Carriage lasts on average $1/\gamma$ days, after which individuals return to compartment $S_i$. These individuals can become carriers again.

Given vaccine effectiveness $V_e$ against IMD, when a proportion $v_c$ of individuals in age group *i* is vaccinated, a proportion $v_c:V_e$ of non-carrier individuals move to the compartment of vaccinated non-carrier individuals $V_i$. Similarly, a proportion $v_c:V_e$ of carrier individuals move to the compartment of vaccinated carriers $C_v$. In these compartments, individuals are protected against IMDs. Individuals in the

<figure><img src="image_4.png" /><figcaption>Fig. 1. Schematic illustration of the model. The model is structured by age group, with groups of 1 year ($i = 1..0.85$). Individuals susceptible in compartment $S_i$ can become carriers of a meningococcus with a rate $\lambda_i$. A proportion of those who become carriers develop IMD. Carriage has an average duration of $1/\gamma$. A proportion of vaccinated individuals move into compartment $V_i$ (if they are not carriers) and $C_v$ (if they are carriers). After an average duration of $1/w$, vaccinated individuals lose the protection conferred by the vaccine, moving into compartments $W_i$ or $CW_i$. Individuals receiving a booster dose move back into compartment $V_i$ or $C_v$.</figcaption></figure>
non-carrier vaccinated compartment ($V_i$) have a risk of acquiring the bacteria that is reduced by the factor $1-Ve^{*carriage}$ compared to unvaccinated non-carriers ($Ve^{*carriage} = Ve_{carriage}/Ve$ to correct for the fact that a proportion 1-Ve of vaccinated individuals goes directly into compartments $W_i$ or $CW_i$ with loss of immunity described below).

To model waning immunity, we assume that after an average duration of 1/w days, vaccinated non-carrier individuals ($V_i$) move to the compartment of vaccinated non-carriers with waning immunity ($W_i$), and vaccinated carrier individuals ($CV_i$) move to the compartment of vaccinated carriers with waning immunity ($CW_i$). Individuals who have lost their vaccine-induced immunity ($W_i$) have the same risk of acquisition and invasive infection as non-vaccinated individuals ($S_i$). The distribution of booster doses is modelled in the same way as primary vaccination by moving a fraction of individuals $bc_i \cdot Ve$ from compartments $W_i$ and $CW_i$ to compartments $V_i$ and $CV_i$, respectively.

## 2.2. Data used to inform the model, force of infection $\lambda_i$ and probability that a carriage event leads to an IMD reconstruction

We define birth cohorts of one year age. For each birth cohort $i$ the full cohort moves from age group $i$ to age group $i+1$ on January 1st of

each year. We informed our model with demographic data and projections from the National Institute for Statistics and Economic Studies (INSEE) for the next 40 years, i.e., until 2065 [10]. A population correction is applied each year to each age group on January 1st to account for deaths and population migration (foreigners moving to France or French citizens moving abroad) to replicate the evolution of the age pyramid over time in France. We assume that migrant populations have the same history of carriage and vaccination as those who have always resided in France.

In the absence of data describing meningococcal carriage in France, we assume that the carriage prevalence by age group in France during the pre-vaccination period is identical to the carriage characterised by Christensen et al. [11] in a meta-analysis from 2010 that excludes studies from Africa, Asia, and Russia (Fig. 2A). Christensen et al. describe the carriage of all serogroups in those under 75 years old. We use a linear regression performed between 60 and 74 years old to estimate the carriage level beyond 75 years old. Because distribution across serogroups is unknown, when studying a specific serogroup, we obtain the proportion of carriers for this serogroup for age group $i$ by adjusting Christensen et al. data with an assumption about the proportion of carriers colonised by that serogroup of interest. Proportions of 10 %

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Data used to calibrate the model. Meningococcal carriage prevalence by age from Christensen et al. [11] (Panel A). Annual number of IMD cases due to serogroups B, C, W, and Y reported in France between 2002 and 2019 (Panel B). Age distribution of IMD-B cases (Panel C), IMD-C cases (Panel D), IMD-W cases (Panel E), and IMD-Y cases (Panel F) in France, between 2002 and 2019 (except for IMD-C: 2002–2010), observed and modelled.</figcaption></figure>
(baseline assumption), 1 %, and 30 % were explored [12]. The terms of the force of infection by age group and serogroup are estimated under the assumption that the epidemic is in a stationary state during the pre-vaccination period [7] (see Supplementary Fig. S1 and Supplementary Material). The duration of carriage (1/γ) is assumed to be 130 days, with 80 days and 180 days explored in the sensitivity analysis [13].

Once the carriage level by age group and serogroup is specified in the pre-vaccination period, we estimate the probability that a carriage event leads to an IMD for each age group and serogroup by calculating the ratio between the number of reported IMD cases in France from 2002 to 2019 for serogroups B, W, and Y (from 2002 to 2010 for serogroup C) and the estimated number of carriage events over this period (Fig. 2B and Fig. S2). Figs. 2C-F show the age distribution of IMD cases for different serogroups in France between 2002 and 2019 (except for cases of IMD-C: 2002–2010), observed and modelled [7]. The modelled age distribution is done by using a smoothing procedure similar to the one used in [3] (see Supplementary Material), to better capture the overall trends in age-specific IMD incidence.

## 2.3. Assumptions about vaccine effectiveness against IMD and carriage

Assumptions about vaccine effectiveness against IMD and against carriage used in the model are reported in Table 1. They reflect the evidence available in the literature regarding vaccine effectiveness against IMD (Ve), vaccine effectiveness against carriage (Ve<sub>carriage</sub>) as well as regarding the average duration of protection. While various brands of vaccines are available, particularly for serogroup ACWY, it is assumed that different parameters, such as vaccine effectiveness, are comparable across different vaccines for the same age group. Notably, in the model we assume no effectiveness against carriage for 4CMenB [14]. While the vaccine effectiveness parameters are identical for both age groups considered (0–10 years and 11+ years) when targeting a specific serogroup, the rate at which protection wanes differs between them. As a result, the overall vaccine effectiveness at the population level varies depending on the age at which the vaccine is administered. In this work, we do not differentiate between the effectiveness values (Ve and Ve<sub>carriage</sub>) of the primary vaccination series and the booster dose. Here, booster doses refer specifically to vaccinations administered during adolescence to individuals who had already received the primary series in infancy.

## 2.4. Vaccination strategies

We modelled the impact of quadrivalent ACWY meningococcal vaccine targeting serogroups Y and W, as well as the impact of the vaccine targeting serogroup B. We assume that the introduction of these vaccines takes place starting 1st of January 2024. Additionally, we assume that all vaccinated individuals receive the required number of doses for the respective vaccine. When vaccination strategies target a

specific age group, we assume that individuals are vaccinated as soon as they reach this age and that there is no delay between vaccination and vaccine protection. In the base-case scenarios, estimates of vaccine coverage for infants were derived from the real coverage observed in France for MenB or MenC vaccination, assuming that the coverage for the ACWY vaccine would be comparable to the one currently observed for MenC after 2018, when vaccination targeting serogroup C became mandatory [24]. For the ACWY and B adolescent vaccination strategies, our scenarios were informed by the current vaccine coverage data for Human Papillomavirus [24]. For the catch-up vaccination, we used the vaccine coverage observed for the MenC catch-up vaccination implemented after 2010. The complete list of scenarios for the ACWY vaccination and the vaccine targeting serogroup B is provided below. For each simulated strategy, we present the expected yearly reduction in cases, the cumulative reduction in the number of cases over different time windows since the start of the vaccination campaign (5, 10, 20, and 40 years), and the number of cases averted per 10,000 vaccinations over the same time periods.

Furthermore, we validate the model by comparing observed and predicted dynamics of the number of serogroup C IMD cases following the introduction of vaccination targeting serogroup C, taking into account the coverage reached for each cohort from 2010 to 2022.

### 2.4.1. Quadrivalent vaccination ACWY

Vaccination strategies targeting serogroups ACWY are defined by the combination of strategies for infants (N), adolescents (AD), and a potential catch-up campaign (R).

* Strategies for infants: Vaccines administered at 12 months (N12m) or 6 months (N6m) with a vaccine coverage of 95 % (baseline strategy). We also examine strategies where infants are not vaccinated (N0).

* Strategies for adolescents:

* ADO: No vaccines administered to adolescents;

* AD11y: Vaccines administered to 11-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %);

* AD14y: Vaccines administered to 14-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %).

In these strategies for adolescents, the vaccine becomes a booster dose 11–14 years after the start of the vaccination campaign.

* Catch-up campaign:

* When R is absent, the scenario corresponds to no catch-up campaign;

* R: Catch-up in 2024, the year the campaign starts, for age groups 15 to 24, assuming that vaccine coverage decreases by 10 % for each additional year of age. When the catch-up is added to strategy AD1, age groups between 12 and 14 are vaccinated with a uniform

<table><caption>**Table 1**

Assumptions about vaccine effectiveness and sources.</caption><thead><tr><th>Vaccine</th><th>Target serogroup</th><th>Age</th><th>Vaccine effectiveness against IMD Ve (%)</th><th>Vaccine effectiveness against carriage Ve<sub>carriage</sub> (%)</th><th>Average duration of protection** (months)</th><th>Ref.</th></tr></thead><tbody><tr><td>4CMenB</td><td>B</td><td>0–10</td><td>82.8*</td><td>0</td><td>38</td><td>[7,14–17]</td></tr><tr><td>4CMenB</td><td>B</td><td>11+</td><td>82.8*</td><td>0</td><td>103 (sensitivity: 48)</td><td>[7,14,16–18]</td></tr><tr><td>MenACWY</td><td>CWY</td><td>0–10</td><td>79</td><td>36.2 (sensitivity: 18.1)</td><td>48</td><td>[7,19,20] [21]</td></tr><tr><td>MenACWY</td><td>CWY</td><td>11+</td><td>79</td><td>36.2 (sensitivity: 18.1)</td><td>187</td><td>[7,19] [13,22,23]</td></tr><tr><td>MenC</td><td>C</td><td>0–10</td><td>87</td><td>50 or 30</td><td>No waning or waning equal to MenACWY for the age group 0–10 years old</td><td>[17]</td></tr><tr><td>MenC</td><td>C</td><td>11+</td><td>87</td><td>50 or 30</td><td>No waning or waning equal to MenACWY for the age group 11+ years old</td><td>[17]</td></tr></tbody></table>

<footnote>* For 4CMenB vaccine, VE includes both the strains covered and those not covered by 4CMenB.</footnote>

<footnote>** extrapolated from immunogenicity studies showing antibody persistence.</footnote>
coverage of 40 % (baseline strategy) (sensitivity analysis: 20 %, 60 %).

### 2.4.2. Vaccination targeting serogroup B

Vaccination strategies for Men B are defined by the combination of strategies for infants (NB), adolescents (ADB), and a potential catch-up campaign (R).

* Strategies for infants: Vaccines administered at 6 months (NB6m) with a vaccine coverage of 70 % (baseline strategy, 55 %–85 %). We also explore strategies where infants are not vaccinated (NB0), disregarding current recommendations for infants.

* Strategies for adolescents:

* ADB0: No vaccines administered to adolescents;

* ADB11y: Vaccines administered to 11-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %);

* ADB14y: Vaccines administered to 14-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %);

* ADB16y: Vaccines administered to 16-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %);

* ADB18y: Vaccines administered to 18-year-old adolescents with a vaccine coverage of 40 % (baseline strategy) (sensitivity analyses: 20 %, 60 %).

In adolescents strategies, the vaccine becomes a booster dose 11–18 years after the start of the vaccination campaign.

* Catch-up campaign:

* When *R* is absent, the scenario corresponds to no catch-up campaign;

* R: Catch-up the year the campaign starts (2024) for age groups between the age selected for adolescent vaccination (e.g., 11 years

for strategy ADB1) and 24 years, assuming that vaccine coverage decreases by 10 % for each additional year of age.

## 3. Results

### 3.1. Impact of quadrivalent ACWY vaccination on IMD-W and IMD-Y cases

Fig. 3 shows the impact of quadrivalent ACWY vaccination on IMD-W cases. In the absence of quadrivalent ACWY vaccination, the number of IMD-W cases will remain stable in the coming years. In strategies where the vaccine is administered to 95 % of infants without vaccinating adolescents (strategies N12m_AD0 and N6m_AD0), the direct protection conferred by infant vaccination leads to a rapid reduction in the number of IMD-W cases, by 8 % (N12m_AD0) to 12 % (N6m_AD0) after 2 years. Performance is marginally better when targeting 6 months old infants (N6m_AD0) compared to 1 years old (N12m_AD0). In the long term, the impact of these two strategies is equivalent.

In strategies targeting only infants, we note a slow decrease in the number of IMD-W cases (35 % reduction after 20 years for N6m_AD0). In contrast, the decrease is much faster in strategies where 40 % of adolescents are also vaccinated (strategies N6m_AD11y and N6m_AD14y) with reductions in incidence by 82–88 % after 20 years. In these strategies, performance is marginally better when vaccinating 14 year olds (88 % reduction after 20 years, strategy N6m_AD14y) than 11 years olds (82 % reduction after 20 years, strategy N6m_AD11y).

If adolescents are vaccinated without vaccinating infants (strategy N0_AD14y), the number of IMD-W cases remains stable for several years after the start of the vaccination campaign. After 5 years, once the proportion of vaccinated adolescents becomes sufficiently large, the number of IMD-W cases begins to decrease, reaching an 80 % reduction after 20 years. To more clearly show this impact, we present in Fig. S3 the expected cases and annual reduction for the age groups <1 year old and < 2 years old. It is worth noting that in the strategy where only

<figure><img src="image_6.png" /><figcaption>Fig. 3. Expected evolution of the number of cases and reduction in the number of cases for ACWY vaccination strategies. Expected evolution of the yearly number of IMD-W cases (Panel A) and IMD-Y cases (Panel B), and yearly reduction in these numbers (IMD-W: Panel C; IMD-Y: Panel D) compared to the no vaccination (N0_AD0) strategy, for different ACWY vaccination strategies starting in 2024.</figcaption></figure>
adolescents are vaccinated (N0_AD14y), a 79 % reduction in the number of cases is observed after 20 years for both age groups.

Adding a catch-up campaign for adolescents from 15 to 24 years olds to the vaccination strategy targeting infants and adolescents (strategy N6m_AD14y_R) leads to a faster decline in the number of IMD-W cases, with reductions of 52 %, 74 %, and 93 % after 5, 10, and 20 years, respectively, compared to 29 %, 57 %, and 88 %, respectively, in the strategy without catch-up (N6m_AD14y).

The expected impact of Men ACWY vaccination on serogroup Y is generally similar to the one described above for serogroup W, with one minor difference. Indeed, for serogroup W, in the short term, strategies targeting only infants are more effective than those targeting only adolescents, with the trend reversing after 5 years. For serogroup Y, both strategies have an identical impact in the early years. After 4 years, strategies targeting only adolescents show better performance. These differences are explained by the fact that, for serogroup Y, there are fewer IMD-Y cases in young children than for serogroup W (Figs. 2E-F).

Fig. 4 presents the reduction in the number of IMD-W cases and the number of IMD-W cases averted per 10,000 vaccinations with Men ACWY vaccine, averaged over the first 5, 10, 20, and 40 years of the vaccination campaign. As expected, over all time periods, the reduction in the number of IMD-W cases is maximum when combining infant and adolescent vaccination with a catch-up campaign (N6m_AD14y_R). This strategy also maximises the number of cases averted per 10,000 vaccinations during the first 5 years of the campaign. For evaluation periods equal to or greater than 10 years, the number of cases averted per 10,000 vaccinations is maximum when vaccinating only adolescents. The superiority of this strategy compared to other strategies increases along with the evaluation period. For example, after 20 years, for 10,000 vaccinations, 0.39 cases of IMD-W are averted with strategy N0_AD14y compared to 0.14–0.16 cases with strategies that also vaccinate infants. We obtain similar results for serogroup Y (Supplementary Fig. S4).

## 3.2. Impact of vaccination targeting serogroup B

Fig. 5 describes the expected evolution of the number of IMD-B cases for different vaccination strategies targeting serogroup B. In the absence of Men B vaccination (strategy NB0_ADB0), the model anticipates that the number of IMD-B cases will remain stable in the coming years. By vaccinating 70 % of 6-month-old infants (NB6m_ADB0), a rapid reduction in the number of IMD-B cases is predicted. However, the reduction remains relatively modest and stabilises at 11 % after 5 years.

If 40 % of 16 year old adolescents are also vaccinated (NB6m_ADB16y), the predicted reduction in the number of IMD-B cases increases to 16 % after 5 years. Given the age distribution of cases, vaccinating 16 year old adolescents offers marginally better reductions than 11 (13 %; NB6m_ADB11y), 14 (15 %; NB6m_ADB14y), and 18 year old (15 %; NB6m_ADB18y). Adding a catch-up campaign for 17–24 year old adolescents to a campaign targeting 6-month-old infants and 16 year olds (NB6m_ADB16y_R) accelerates the reduction in the number of IMD-B cases, which reaches 16 % by the 3rd year of the campaign.

Fig. 6 shows the reduction in the number of IMD-B cases and the number of IMD-B cases averted per 10,000 vaccinations for different evaluation periods. The ordering of strategies remains stable for different evaluation periods. Vaccinating only adolescents (NB0_ADB16y) is the least effective strategy, irrespective of the evaluation criterion. Vaccinating infants, 16 year old adolescents, and implementing a catch-up campaign (NB0_ADB16y_R), leads to the most important reductions in the number of IMD-B cases. However, the number of cases averted per 10,000 vaccinations is maximum when vaccinating only infants (NB6m_ADB0) with 0.65 cases averted per 10,000 vaccinations during the first 10 years of the campaign.

## 3.3. Sensitivity analysis

Fig. 7 shows how the modelling results are impacted when changing

our assumptions regarding vaccine coverage, proportion of carriers colonised by the serogroup of interest and duration of carriage for the quadrivalent ACWY vaccine and the vaccine targeting serogroup B.

In Fig. 7A, we show the impact of varying vaccination coverage for adolescents in the case of quadrivalent vaccination against serogroup W, 10 years after the implementation of the campaign. The expected reduction in the number of cases under the strategy N6m_AD14y_R increased from 43 % to 52 % when adolescent vaccination coverage increased from 40 %, in the baseline assumption, to 60 %. Conversely, the expected reduction is 31 % in the case of 20 % vaccination coverage for adolescents. Similar results are shown in Fig. 7B, considering serogroup Y.

Regarding vaccination against serogroup B, for the strategy NB6m_ADB16y, increasing the vaccination coverage for adolescents from 70 % to 85 % will increase the expected reduction in IMD cases from 13 % to 15 % (Fig. 7C).

Fig. S5 shows the evolution of the yearly reduction in cases over time, starting from the launch of the vaccination campaign in 2024, for different vaccine coverage levels among adolescents (for both ACWY and serogroup B vaccinations) and children (for serogroup B vaccination).

For ACWY vaccination, increasing adolescent coverage significantly accelerates the yearly reduction in cases. For example, under the N6m_AD14y_R strategy targeting IMD-W (Fig. S5A), a 93 % reduction in cases is achieved after 14 years with 60 % adolescent coverage, compared to 20 years with the baseline 40 % coverage. In contrast, if adolescent vaccine coverage is reduced to 20 %, the same level of reduction is expected only after 35 years.

For vaccination targeting serogroup B, increasing the coverage of children to 85 % (compared to the baseline of 70 %) would enhance the impact by approximately 2 % after 5 years, increasing the reduction in cases from 11 % to 13 % (Fig. S5C). Conversely, reducing the coverage to 55 % would decrease the impact by about 2 %, lowering the reduction from 11 % to 9 %. Similarly, increasing the vaccination coverage of adolescents from 40 % (baseline) to 60 % would raise the reduction in cases from 16 % to 18 % after 5 years under the NB6m_ADB16y strategy (Fig. S5D). Reducing the coverage to 20 % would lower the reduction to 13 %.

We found that varying assumptions on the proportion of carriers and the duration of carriage only slightly modified the order of strategies (Fig. 7E-F, and Fig. S6) for the serogroup W and Y. No change is observed for the strategies targeting serogroup B (Fig. 7G-H). The impact of vaccination is less pronounced for IMD-W when increasing the duration of carriage (Fig. 7F). For example, in the strategy combining infant and adolescent vaccination with a catch-up campaign (N6m_AD14y_R), the expected reduction in IMD-W cases after 10 years decreases from 43 % to 37 % when the duration of carriage is set to 180 days compared to baseline 130 days assumption.

We also tested the impact of the assumption on carriage for the different quadrivalent ACWY vaccination strategies, using the upper and lower bounds of the distribution from Christensen et al. [11] (Fig. 2A), instead of the average value used in the baseline analysis (Fig. S7). The impact on the strategies remained very limited, with only a difference of a few percentage points observed within the explored time window. These small percentage changes did not affect the relative ranking of the strategies, which remained unchanged when comparing them under the same set of assumptions related to carriage by age (Fig. S7). Strategies involving infant vaccination (N6m_AD0 and N12m_AD0) led to very similar results when the assumption on carriage by age was varied, making their long-term outcomes difficult to distinguish from one another (Fig. S7). No difference is expected for the strategies targeting serogroup B, consistent with the findings from the other sensitivity analyses on the proportion of carriers for serogroup B and the duration of carriage (Fig. 7G–H).

Changing the assumption on vaccine effectiveness against carriage for the quadrivalent vaccination ACWY, from 36.2 to 18.1, changed the
<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Reductions in the cumulative number of cases of IMD-W in orange and number of vaccinations administered in blue (left hand side column) and numbers of cases of IMD-W averted per 10,000 Men ACWY vaccinations (right hand side column), over the first 5 (Panel A-B), 10 (Panel C-D), 20 (Panel E-F), and 40 (Panel G-H) years of the vaccination campaign. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Expected evolution of the yearly number of cases of IMD-B (Panel A), and yearly reduction in this number (Panel B) compared to the strategy "absence of vaccination" (NB0_ADB0), for different strategies of vaccination targeting serogroup B starting in 2024.</figcaption></figure>

expected impact of the different strategies in terms of yearly or cumulative case reduction within the evaluated time windows (Figs. S8-S10). However, importantly, it did not change which strategy was the most effective in terms of cases averted per 10,000 vaccinations (Figs. S9-S10). As in the baseline analysis, the strategy NB6m_AD14y_R yields the highest number of cases averted per 10,000 vaccinations during the first 5 years of the campaign, while for evaluation periods of 10 years or longer, the greatest impact per 10,000 vaccinations is achieved by vaccinating only adolescents (N0_AD14y).

Changing the average duration of protection for adolescent vaccination targeting serogroup B had a minimal impact on the results, reducing the expected yearly case reduction after 5 years by only 2%, from 16% to 14% for NB6m_ADB16y (Fig. S11). In terms of the strategy that maximises impact, NB6m_ADB0 remains the most effective, as in the baseline scenario, yielding the highest number of cases averted per 10,000 vaccinations (Fig. S12).

### 3.4. Model Validation - Impact of vaccination targeting serogroup C from 2010 to 2022

We validated the model by comparing the observed dynamics of IMD-C cases since the introduction of vaccination targeting the serogroup C with those predicted by the model (Fig. 8). Given uncertainties about the waning of immunity for Men C vaccines, we explore two strategies. In the absence of waning of immunity, there is a good fit between the model and the observed long-term trend in the data (Fig. 8A). In the strategy where the waning of immunity for Men C serogroup vaccines is equal to that measured for quadrivalent ACWY vaccines (Fig. 8B), the model captures the long-term trend until 2019, and then a divergence is noted from 2020 onwards, with predictions

exceeding the reported number of cases. This divergence could be explained by the impact of non-pharmaceutical measures implemented in 2020 to limit the transmission of SARS-CoV-2, which may have also limited the transmission of meningococci and infection by the bacteria [1]. Overall, these two strategies suggest a good alignment of the model with the data.

## 4. Discussion

In this paper, we used a mathematical model to estimate the impact of introducing a quadrivalent ACWY vaccination strategy or of modifying the serogroup B vaccination strategy currently targeting infants. A large range of vaccination scenarios were tested alone or in combination, namely infants and/or adolescents with or without a young adult catch-up.

For ACWY vaccination, the model estimates that targeting infants and adolescents, along with a catch up campaign for individuals aged 15 to 24, is not only the most effective strategy for reducing IMD W and IMD Y cases but also the most efficient over the first 5 years of the program, measured by the number of cases averted per dose. This approach is projected to reduce the incidence of IMD-W and IMD-Y by approximately 50% (52% and 48%, respectively) during this period. Within 20 years, the reduction of the number of IMD-W and IMD-Y cases would be 93%, approaching elimination. However, 10 years after the start of the campaign, the number of cases averted per 10,000 vaccinations is highest when targeting only adolescents. This reflects the positive impact of herd immunity induced over the years by adolescent vaccination, protecting the young infants, therefore making their direct protection less and less necessary. This suggests that to maximize public health benefits while minimizing costs, it could be relevant to start by targeting infants and adolescents and implementing a catch-up campaign in 2024 and, after 10 years, transitioning to vaccinating only adolescents, provided that a high enough vaccination coverage has been reached and sustained in this age-group. Given the age distribution of carriers and cases, the model finds it preferable to vaccinate 6-month-old infants rather than 1 year olds, and, based on the estimated duration of protection of the adolescent dose, 14 year old adolescents rather than 11 year olds. However, for both ages, the differences between the two options are small.

The model predicts that relative reductions in IMD cases will be substantially smaller for Men B than for Men ACWY. Even in the long run, the overall reduction of IMD-B cases in all studied scenarios remains below 20%. This is because, unlike quadrivalent ACWY vaccines, serogroup B vaccines do not prevent carriage acquisition [14,17]. As a result, vaccine effectiveness against carriage is assumed to be zero in the modelling framework for vaccination targeting serogroup B (Table 1), and therefore no indirect protection is provided. Vaccinating only infants maximises the number of cases averted per 10,000 vaccinations. Conversely adding an adolescent and a young adult catch-up vaccination only increases the impact by 5%, even in the long run.

Because of the lack of availability of data describing meningococcal carriage in France, we used the data provided in a meta-analysis from 2010 [11]. Such data encompass carriage of both virulent and non virulent strains which may differ substantially in terms of duration of carriage. In the absence of data, we also assumed that carriage dynamics of different serogroups reached a steady state in the pre-vaccination period. These are strong assumptions that could impact the predicted dynamics and therefore the model results regarding vaccination impact. In our sensitivity analysis, we showed that the results were robust in all the scenarios when varying assumptions regarding the contribution of different serogroups to carriage, carriage durations, and when using the upper and lower bounds of the prevalence of carriage by age, a reas-uring result.

Future studies documenting meningococcal carriage in France will be key to improve our understanding of meningococcal epidemiology in France and allow refining our evaluations of vaccine impact.
<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Reductions in the cumulative number of cases of IMD-B in orange and number of vaccinations administered in blue (left hand side column) and numbers of cases of IMD-B averted per 10,000 targeting serogroup B (right hand side column), over the first 5 (Panel A-B), 10 (Panel C-D), 20 (Panel E-F), and 40 (Panel G-H) years of the vaccination campaign. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

(caption on next page)
**Fig. 7.** Sensitivity analysis. Sensitivity analysis showing how reductions in the cumulative number of cases of IMD-W, IMD-Y, and IMD-B after 10 years since the start of the vaccination campaign in 2024 are modified when assumptions about vaccine coverage, proportion of carriers and duration of carriage are changed. Panels A and B: For ACWY vaccination, vaccine coverage for adolescents is 40 % (baseline strategy), 20 %, 60 %; for infants aged 6 months and 1 year, vaccine coverage remains fixed at 95 %. Panel C: For vaccine targeting serogroup B, vaccine coverage for infants is: 70 % (baseline strategy); 55 %; 85 %. Panel D: For vaccination targeting serogroup B, vaccine coverage for adolescents is 40 % (baseline strategy), 20 %, 60 %. Panel E: Reductions in the number of cases of IMD-W after 10 years for different assumptions about the proportion of carriers colonised by the serogroup of interest (10 %, 1 %, 30 %) for serogroup W. Panel F: As in Panel E but for different assumptions on the duration of carriage (130, 80, and 180 days). Panel G: as in Panel E but for serogroup B. Panel H: as in Panel F but for serogroup B.

<figure><img src="image_18.png" /></figure>

**Fig. 8.** Number of annual cases of IMD-C observed and predicted by the model for different assumptions regarding vaccine efficacy (30 %, 50 %) and the decline of immunity for vaccines targeting serogroup C (Panel A: scenario with no decline; Panel B: scenario with a decline equal to that estimated for quadrivalent ACWY vaccines).

Data describing the epidemiology of IMD cases in France come from an exhaustive and stable surveillance system. Exhaustiveness has been assessed several times as above 90 %, through two different capture-recapture studies performed in 2005 and in 2011 [25,26]. Indeed, there is an obligation for health care professionals to notify the local health authority in case of a suspicion or a confirmation of an IMD in order to allow the implementation of the urgent control measures for close contacts, mainly antibioprophylaxis and vaccination.

In the baseline scenario, we assumed that infant coverage would be similar to the coverage of the MenC vaccine or other vaccines administered at similar ages for adolescent and adult catch-up programs. Estimates for infants came from the Health Certificates database, completed mandatorily for all children at 24 months. Data for older age groups were sourced from the national drug and vaccine reimbursement database, as almost all vaccines for individuals aged 10–24 are administered privately.

Given uncertainty about achievable vaccine coverage, we presented multiple possible scenarios in sensitivity analyses. We have identified specific target age groups to maximize the impact of a vaccination campaign. For children, we chose to focus on vaccination strategies for infants at 1 year of age, excluding strategies targeting children aged 2 years or older. This decision was informed by the epidemiology of IMD and prevalence of bacterial carriage. Children under 2 years are most affected by IMD and require direct protection. However, from the perspective of indirect immunity, children less than 5 years old exhibit low levels of bacterial carriage (Fig. 2A), making them an unsuitable target for strategies aiming to reduce transmission through herd immunity. In contrast, adolescents are a critical target group for achieving indirect immunity. They have high levels of meningococcal carriage,

serving as a primary reservoir for transmission within the population. Vaccinating adolescents might significantly reduce bacterial carriage in the population, interrupting the transmission chain, reducing disease risk across all age groups through herd immunity and approaching elimination as demonstrated by our modelling framework. However, as adolescent vaccine coverage may be limited, we choose to consider it in the model at 40 % (baseline scenario) based on the current coverage of HPV vaccination coverage for adolescents, which could delay the full impact of herd immunity. The sensitivity analysis further illustrates this point: when adolescent vaccination coverage was varied from 40 % (baseline) to either 60 % or 20 %, the expected 93 % reduction observed after 20 years in the baseline analysis was instead reached after 14 and 35 years, respectively. These results highlight the role of indirect protection associated with adolescent coverage (Fig. S5A-B). In such a situation, it will take time for the reduction in bacterial carriage among adolescents to effectively lower IMDs and provide indirect protection to infants. Until herd immunity is established and begins to protect infants, it remains critical to ensure their direct protection against IMD. For this reason, practical aspects such as timing within the vaccination schedule and achieving high vaccine coverage in adolescents must be carefully considered. In France, for instance, vaccination is typically conducted during doctor appointments on a voluntary basis, without widespread campaigns in schools or colleges. This approach contrasts with that of some other countries, where school-based vaccination programs are implemented to achieve broader coverage.

Although this model provides a useful framework for studying the dynamics of meningococcal carriage, it has several limitations that must be acknowledged. First, it assumes that invasion occurs solely at the time of acquisition, without considering the possibility of a latent period or
subsequent infection. Second, analyzing data on an annual basis may mask important temporal patterns, such as seasonal effects related to climate or co-infections with other pathogens. Several studies have demonstrated that such factors can significantly influence IMD dynamics, with evidence suggesting that co-circulating infections like influenza play a role in shaping seasonal trends, and that vaccination may also contribute to shifts in these patterns [27–30]. However, for these two points, the model is specifically calibrated to reproduce the average observed IMD cases incidence by age class from previous years and then aggregate the expected annual number of IMD cases. As a result, short-term temporal variability or delays between acquisition and infection is not expected to significantly impact the results of the study. The duration of carriage remains poorly documented and may vary by age and serogroups, introducing additional uncertainties. Conducting longitudinal studies could help address this gap and refine the model. Moreover, the model has no spatial structure, therefore overlooking localized clusters or outbreaks, which are known to occur in meningococcal disease. The assumption that the epidemic is in a stationary state may overlook changes in the epidemiology of meningococcal disease. For example, carriage disruption likely introduced by the COVID-19 pandemic [1] and the resulting transient dynamics may influence short-term estimates of the effectiveness of the new vaccine campaign. We assume that migrant populations have the same history of carriage and vaccination as individuals who have always resided in France. While this may appear to be a strong assumption, we believe its impact on the results would be minimal, given that the annual volume of migration remains limited relative to the overall resident population in France. Finally, the model treats different strains independently, neglecting possible interactions between strains and the effects of immunity or vaccination. Due to limited data on meningococcal carriage over time, particularly regarding the magnitude and speed of potential strain replacement, incorporating these aspects into model calibration is challenging and further studies should be done to analyze serogroup replacement possibly induced by vaccination.

For both vaccinations against serogroup B and serogroup ACWY, the model primarily focused on estimating the reduction in the number of IMD cases. However, we anticipate a significant positive impact on severe morbidity and mortality due to the reduction in IMD cases incidence, including a reduction in deaths and children facing lifelong complications.

Other studies evaluated the impact of a quadrivalent adolescent vaccination in other countries, reaching conclusions similar to the current study. In the UK, a study by Beck et al. [7] showed that vaccinating children alongside adolescents results in only a marginal reduction in cases associated with serogroups ACWY. In Chile, where quadrivalent vaccination is administered to one-year-old infants, the study of Grana et al. [31] showed that replacing or adding a dose of the quadrivalent vaccine targeting serogroups ACWY for adolescents does not provide additional short term benefits in reducing the incidence of invasive meningococcal disease. However, these strategies offer a long-term impact over 25 years.

Our results supported the recommendations of the French National Authority for Health, which were endorsed by the Ministry of Health. Since January 2025, the 2 doses of Men C vaccination included in the routine vaccination schedule for infants less than 2 years of age were replaced by 2 doses of ACWY vaccination. A single dose for adolescents was introduced between 11 and 14 years of age (which will act as a booster when the first cohort of infants vaccinated with the quadrivalent vaccine will reach adolescence). The 11–14 age range was chosen, rather than the 14 years old, in order to allow more opportunities for vaccination, especially as this same age range corresponds to that of the DTaP-Polio booster and of the HPV vaccination. Furthermore, plans are underway to implement a school-based ACWY quadrivalent vaccination for Grade 7 students as of 2025. Last, a catch-up for 15 to 24 years old was also introduced. No change in the schedule for Men B vaccination was made.

This evaluation showcases how modelling can be used to inform evidence-based decision making on vaccines, providing valuable insights for health authorities in France and in other countries as they revisit their vaccination strategies against IMD.

### CRediT authorship contribution statement

**Paolo Bosetti:** Writing – original draft. Visualization, Validation, Software, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. **Laurène Peckeu-Abboud:** Writing – review & editing, Project administration, Data curation. **Roland Michel Andrianasolo:** Writing – review & editing, Project administration, Data curation. **Marc Baguelin:** Writing – review & editing, Software, Methodology, Investigation. **Laure Fonteneau:** Writing – review & editing, Resources, Data curation. **Ala-Eddine Deghamne:** Writing – review & editing, Data curation. **Muhamed-Kheir Taha:** Writing – review & editing, Data curation. **Anne-Sophie Barret:** Writing – review & editing, Data curation. **Emmanuel Grimprel:** Writing – review & editing, Validation. **Lulla Opatowski:** Writing – review & editing, Methodology, Investigation. **Daniel Lévy-Bruhl:** Writing – review & editing, Validation, Investigation. **Simon Cauche-mez:** Writing – original draft, Supervision, Investigation, Formal analysis, Conceptualization, Funding acquisition, Methodology.

### Declaration of competing interest

M.K. Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi Pasteur. M.K. Taha and A.E. Deghamane has a patent NZ630133A Patent with GSK "Vaccines for serogroup X meningococcus" issued. L.O. received research grants by Sanofi and Pfizer through Institut Pasteur on unrelated topics.

### Acknowledgments

This project was supported by the French National Authority for Health, the European Commission under the EU4Health programme 2021–2027 (grant 101102733–DURABLE), the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases programme (grant ANR-10-LABX-62-IBEID), and the INCEPTION project (grant PIA/ANR16-CONV-0005).

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2025.127871.

### Data availability

Data will be made available on request.

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