Evaluation of a temporary vaccination recommendation in response to an outbreak of invasive meningococcal serogroup C disease in men who have sex with men in Berlin, 2013–2014

J Koch 1 , W Hellenbrand 1 , S Schink 1 , O Wichmann 1 , A Carganico 2 , J Drewes 3 , M Kruspe 3 , M Suckau 4 , H Claus 5 , U Marcus 1 1. Department for Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany 2. AIDS working group of practicing physicians Berlin e.V., Berlin, Germany 3. Free University Berlin, Public Health, Berlin, Germany 4. Infectious Disease Protection Unit, Senate Department for Health and Social Affairs, Berlin, Germany 5. University of Würzburg, Institute for Hygiene and Microbiology and National Reference Laboratory for Meningococci, Würzburg, Germany

The overall prevalence of nasopharyngeal meningococcal carriage is about 10%, but varies markedly in different age and population groups [5][6][7][8].Very high Nm carriage rates of over 40% have been reported in men who have sex with men (MSM) [9][10], and one study reported higher carriage rates in MSM (23.8%) than in heterosexual men (11.6%) [11].Further known risk factors for meningococcal disease, such as exposure to tobacco smoke and crowding [12,13], may also be more prevalent in venues where MSM meet.Since 2001, IMD clusters in MSM have been reported in Toronto (2001) [14], Chicago (2003) [15] and New York City (2010-2013) [16][17].All outbreaks were caused by MenC and were of the multilocus sequence type (MLST) 11 (ST-11) [18].The outbreaks in Toronto and Chicago (six cases each) ended rapidly after carrying out targeted MenC vaccination campaigns in the gay communities affected.However, the New York outbreak (22 cases) was more protracted despite intensive efforts to vaccinate MSM.
From October 2012 to May 2013, five IMD cases in MSM living in Berlin were notified to local health authorities (LHA).The patients were between 22 and 28 years old; none were HIV-positive.All cases were caused by MenC strains belonging to ST-11 of the fine type PorA(P)1.5-1,10-8:FetA(F)3-6[19].In addition, four of the five strains from these patients had fHbp allele 766, that had not been described previously.All five cases presented with severe sepsis; four died.Only two of the cases had a definite epidemiological link, having spent a night together shortly before illness onset [19].In this time period MenC clusters among MSM were also reported from New York, Los Angeles and Paris and a single case from Belgium.All European strains showed similar characteristics [20].
It has been estimated that 80,000 MSM (95%CI 74,000-104,000) aged 20-59 years live in Berlin [21][22].Among these, an estimated 10,800 MSM had been diagnosed with HIV as of the end of 2013 [22].Assuming the age distribution among MSM is similar to that of men in the general population, an estimated 18,000 MSM aged 20-29 years live in Berlin, among whom four MenC IMD cases occurred in the first half of 2013.The resulting incidence of 11 cases/100,000 inhabitants [23] was markedly higher than the nationwide incidence of 0.7/100,000 in 20-29 year old men in 2012 [24].
Prevention of IMD with meningococcal conjugate vaccines is highly effective [25].In Germany, MenC vaccination was recommended for all one year-old children in 2006; older children can obtain the vaccine on an individual basis free-of-charge.Vaccination coverage of adolescents increased gradually, reaching 59% among 15-17 year-olds in 2013 based on statutory health insurance (SHI) claims data (Thorsten Rieck, personal communication, January 2015).In addition, vaccination against serogroups ACWY (MenACWY) is recommended for persons with congenital or acquired immunodeficiencies with residual T-and/or B-cell function, especially complement/properdin deficiencies, hypogammaglobulinaemia, and asplenia.While HIV infection is not explicitly listed, it is considered to be an indication for meningoccal vaccination under this rubric.Quadrivalent meningococcal vaccination is also recommended for travellers to endemic areas.Finally, vaccination is recommended to control regional IMD outbreaks when three or more cases of an identical serogroup occur in a specific age group in a particular region within three months in conjunction with an attack rate of 10 or more cases per 100,000 inhabitants in the respective population [26].
Thus, in response to this outbreak, the competent authorities of the federal state of Berlin recommended meningococcal vaccination for all MSM with a vaccine licensed for adults to protect against serogroup C as of 27 July 2013, following advice from the Berlin Advisory Board for Immunisation and announced in a press release on 18 July 2013 [27].Female partners of MSM were not targeted in this recommendation.The recommendation was to remain in effect until 31 January 2014, but was subsequently extended to 31 December 2014, pending an evaluation of its impact.The recommendation did not entail reimbursement of the vaccine by SHI.However, most insurance companies adopted a policy of individual evaluation and reimbursement upon request.The gay community and physicians were informed via internet forums as well as by radio, TV and the print media.The recommendation was promoted in counselling centres of the gay and lesbian community in Berlin, by the German and Berlin AIDS service organisations (DAH and BAH, respectively), the AIDS working group of practicing physicians in Berlin (AK AIDS), the German association of practising physicians treating  HIV-infected patients (DAGNÄ) and via regional and national gay Internet portals.
Our goal was to evaluate the awareness and implementation of the temporary MenC vaccination recommendation for MSM in Berlin by surveying MSM and physicians.In addition, we analysed IMD cases notified in Berlin after implementation of the recommendation, including the molecular epidemiology of MenC cases, to confirm that the outbreak had been interrupted.

Internet-based survey among men who have sex with men
Starting in the late 1980s, anonymous knowledge, attitude and behaviour (KAB) surveys on HIV/AIDS were conducted every two to four years among MSM in Germany [28]; from 2007 onwards these were carried out online exclusively.Questions on the Berlin vaccination recommendation were included in the nationwide survey made available online from November 2013 until mid-January 2014.Participants living in Berlin were asked how they obtained information on the MenC vaccination campaign and whether they obtained vaccination.They were recruited by personalised instant messages and banners on social networking and dating websites for MSM.Two multivariable logistic regression models were constructed to analyse factors potentially associated with awareness of the recommendation and with MenC vaccine uptake, respectively.The following factors were investigated: demographic and behavioural characteristics such as age, educational status, income, reported sexual orientation, openness regarding sexual orientation towards colleagues and their physician, affinity to gay subculture (visiting gay venues), information seeking pertaining to HIV, HIV testing, and HIV status, number of sexual partners in the previous year, and sources used to obtain information on the Berlin vaccination recommendation.Respondents who reported MenC vaccination before the recommendation was issued were excluded from this analysis.
The online survey protocol was evaluated and approved by the ethical review board of the Charité University Clinic in Berlin (EA1/266/13).

Prescription of meningococcal conjugate vaccines
The

Survey of primary care physicians
In February 2014 we conducted a cross-sectional survey among privately practicing physicians belonging to AK AIDS, who represent almost all primary HIV care providers and are known as MSM-friendly.We assumed that most MSM would seek vaccination from one of these practices, which covered a range of relevant medical specialties.The study was presented in January 2014 at the AK AIDS working group meeting to motivate members to participate.Since most members worked in group practices, we conducted the survey per practice.We used a written anonymous questionnaire eliciting participants' demographics (age, sex, physician specialty, location and type of practice), the number of MSM clients and HIV-infected patients in the practice population, information channels used to inform patients, vaccination practices in general and MenC vaccination practices in particular, including type of vaccine used, possible obstacles to immunisation and vaccine uptake by MSM.After pre-testing, the questionnaire was distributed on 14 January 2014 to all 45 practices, with a total of about 70 practicing physicians.Returned questionnaires were entered electronically using Microsoft Excel 2010.We conducted a descriptive analysis, including calculation of proportions and 95% confidence intervals (CI).

Surveillance of invasive meningococcal disease cases in men who have sex with men after meningococcal C vaccine recommendation
In Germany, surveillance of IMD is based on statutory notification by physicians and laboratories to LHAs [29].LHAs transmit laboratory-confirmed and epidemiologically linked IMD cases to the Robert Koch Institute (RKI) via the federal state authorities according to a standardised case definition.These data are routinely matched to data of invasive meningococcal strains that undergo molecular genetic typing at the national reference laboratory for meningococci and Haemophilus influenzae (NRLMHi) as described previously [30].

Internet-based survey among men who have sex with men
MenC-related questions were answered by 1,471 online survey participants.Of these, 42 (2.9%) reported MenC vaccination before the recommendation was published and were excluded from further analysis, leaving a study sample of 1,429 men.
The median age of respondents was 40 years (range: 16-78 years); 72% had at least a high school diploma.
The majority (78%) reported exclusively male sexual partners in the previous 12 months, but only 37% reported regularly visiting gay venues.About half (52%) stated that they were single, 44% reported having a steady male partner, and 4% a steady female partner.Most (81.5%) had been tested for HIV at least once; among those tested (n = 1,199), 23% were HIV-positive.Table 1 presents demographic, behavioural and information-seeking characteristics stratified according to awareness of the recommendation and vaccine uptake.
Of all participants, 852 (59.6%) were aware of the recommendation and 333 (23.3%) obtained MenC vaccination.Positive HIV status, the primary healthcare provider being aware of the respondent's sexual orientation, having received information about the recommendation from a larger number of different information channels, higher educational level, and > 10 sexual partners in the past year were independently associated with both awareness of the recommendation and obtaining vaccination (Table 2).Frequent visits to gay venues were also significantly associated with awareness, while men who reported having mainly female partners were less likely to have heard of the recommendation (Table 2).Over two-thirds (69.6% (183/263) of HIV-infected MSM, but only 12.9% (150/1,166) of non-tested or HIV-negative participants reported obtaining MenC vaccination.
MSM whose physicians personally recommended MenC vaccination during a healthcare visit had the highest vaccine uptake, followed by those who learned of the recommendation through HIV/AIDS information and support organisations.However, only 18.8% (268/1,429) of all survey participants and 31.5% of survey participants aware of the vaccination recommendation (268/852) were exposed to these sources.The highest number of MSM was reached through MSM online and print media, followed by general print and broadcast media, but vaccine uptake among these MSM was lower (Figure 1).

Prescription of meningococcal conjugate vaccines
From

Survey of primary care physicians
Of 45 distributed questionnaires, 30 (66.7%) were returned completed.The respondents' median age was 50 years (range: 41-64 years), 22 were male and six female.The two most common disciplines of the surveyed practices were family (n=12) and internal medicine (n=13), followed by dermatology (n=4).This was similar to the distribution of disciplines among all contacted practices.Responding physicians estimated MenC vaccine uptake to be markedly higher among HIV-infected patients than HIV-non-infected patients in February 2014, ca 6 months after implementation of the recommendation (Figure 3).They administered quadrivalent MenACWY vaccine almost exclusively (28/29) rather than a monovalent vaccine.Twenty-two practices reported that MSM patients sometimes declined MenC vaccination despite the recommendation, most commonly due to a lack of perceived risk, a negative attitude towards vaccination, or fear of side effects (Table 3).Half the responding physicians believed that concerns regarding reimbursement of vaccination costs by SHI led to refusal of the recommended vaccination in approximately onethird of eligible patients in these practices.

Discussion
We evaluated the implementation, acceptance and impact of a temporary MenC vaccination recommendation issued in response to a MenC outbreak among MSM in Berlin in 2013.In the 13 months following endorsement of the recommendation, no further outbreak-related cases were reported among MSM.As LHA elicited sexual orientation of all reported IMD cases, it is unlikely that cases in MSM were missed.The recommendation led to enhanced meningococcal vaccination activities among MSM, but primarily among those with an HIV diagnosis.It seems plausible that the targeted vaccination campaign reduced meningococcal transmission in the population at risk.However, due to the rare and sporadic nature of IMD occurrence, it is possible that the outbreak would have also ended without enhanced vaccination activities.Factors excluded from the model as non-significant: income (≤ EUR1,000 /month vs > EUR 1,000/month); age (≤25 years-old vs >25 years-old).
As IMD clusters in the MSM community seem to be a recurring problem [14][15][16]18], heightened awareness should be upheld during routine surveillance to ensure early detection of and response to outbreaks in this group.All IMD cases should be reported promptly to responsible LHA and sexual orientation elicited during epidemiological case investigation.
The results of the surveys among MSM and physicians and vaccine prescription data showed both directly and indirectly that targeting information to the relevant groups was effective, reaching an estimated 60% of MSM according to the internet-based survey.
Preventive measures such as pneumococcal and influenza vaccination were well established in the everyday practice of physician members of the working group on AIDS, likely facilitating the prompt response to the new recommendation.Almost all responding practices reported offering the recommended MenC vaccine during patient visits.The conditions for the implementation of a new vaccination recommendation were particularly favourable in this network of competent and dedicated physicians with an interest in treatment of HIV-infected patients.For MSM who did not routinely consult such practices, the situation might be different.Their doctors may not have offered meningococcal vaccination due to a lower level of awareness of the recommendation.Nonetheless, estimated vaccination coverage according to participating physicians was similar to that based on analysis of prescription data and the online survey.
The majority of meningococcal vaccinations were administered to HIV-positive MSM, over two thirds of whom were vaccinated based on the internet survey and prescription data, versus only 13% of the HIVnegative or untested internet survey participants.This may reflect less frequent physician contacts in the latter group.In addition, primary care providers also faced healthcare system-and patient-related barriers to vaccine delivery, including uncertainty regarding reimbursement of vaccination costs, fear of side effects and scepticism towards vaccination in general.Being required to at least indirectly reveal their sexual orientation to SHI to receive reimbursement for MenC vaccination may have been a further barrier for patients.
In future similar situations, it might be helpful to communicate more detailed information on vaccine safety and requirements for reimbursement during the initial promotion of the campaign.Convincing SHI companies to directly reimburse vaccination costs in the case of outbreak-related vaccination recommendations and/or to provide funding for anonymous and free communitybased vaccination sites would likely increase willingness to receive vaccination in similar situations.
In agreement with other studies, our survey among MSM showed that personal advice from the physician is pivotal in influencing willingness to be vaccinated [31][32].In this case of a vaccination recommendation being limited to MSM, the physicians' recommendation had an even greater impact when the sexual orientation of the patient was known, emphasising the importance of a trusting doctor-patient relationship.In addition, vaccination could be conveniently obtained at routine healthcare visits, at least in HIV-positive MSM.
In the implementation of a preventive measure such as a vaccination campaign, it is a particular challenge to reach the population most at risk.Our results show that repeated information via different sources led to higher vaccination uptake, similar to the findings of Friedman et al. during a community-wide hepatitis A vaccination campaign [33].Nonetheless, 40% of MSM who participated in the online survey were unaware of the campaign.These men tended to be less open about their sexual orientation, reported less risky sexual behavior and visited gay venues less often.It would still be important to reach this group for targeted prevention measures, and for this, other channels of information must be identified.
Despite the long-standing STIKO recommendation to vaccinate immunocompromised patients against IMD, the majority of HIV-positive online survey participants (96%) were not vaccinated prior to the Berlin MenC vaccination recommendation.Only 20% of physicians in the practice-based survey stated that HIV-related immunodeficiency was an indication for meningococcal vaccination prior to the recommendation.Rather, travel abroad was the most common indication for meningococcal vaccination of MSM.The prescription data showed that MenC vaccine uptake increased in states other than Berlin as well.While this suggests that the Berlin MenC vaccination recommendation increased awareness for the pre-existing STIKO recommendation to immunise HIV-infected persons, more widespread education of physicians is required.
Our study has several limitations.Firstly, the impact of the vaccination campaign could only be determined indirectly through an observed decrease in the number of cases.Due to the sporadic nature of meningococcal clusters, we cannot say definitively that no further cases would have occurred even without vaccination.Studies to investigate the direct impact of vaccination on circulation of the pathogen in the gay community would be extremely difficult to perform since colonisation with MenC is very rare compared to other serogroups [5].In addition, for population groups such as MSM it is impossible to determine the representativeness of an online sample.It is likely that MSM participants in the survey were more socially and sexually active, as well as more open about their sexual orientation, than MSM who did not participate.Such MSM may be more easily reachable by a vaccination campaign promoted through gay media [34][35].However, the remarkable agreement in the estimated proportion of HIV-positive MSM vaccinated after the Berlin recommendation based on the internet survey with prescription data and physicians' estimates suggests that at least HIV-positive MSM were well represented in the survey.

Conclusion
In conclusion, the vaccination campaign launched to control the IMD outbreak in Berlin achieved a marked increase in vaccination coverage in MSM with HIV.The much lower coverage achieved in non-tested or HIVnegative MSM reflects known challenges of outbreak control in specific social groups such as MSM compared to in institutional settings [28].Nonetheless, no further IMD cases occurred in MSM, and ongoing molecular genetic monitoring at the NRLMHi did not detect the outbreak strain in any IMD cases from Germany.A key finding of our study was that receiving information on the campaign from several sources increased vaccination uptake; thus widespread promotion of a new recommendation through all possible venues is crucial to reach target groups.Promotion of such a recommendation should also directly motivate persons in the target group to visit their physician and contact specific support groups, as these measures were associated with the highest vaccine uptake.In particular, the long-standing and effective network of MSM-friendly physicians was crucial in implementing the vaccination campaign.Since lack of perceived risk for IMD and concerns regarding adverse vaccine effects were identified as important barriers to vaccination uptake, these issues should be more specifically addressed in future vaccination campaigns.Finally, in addition to direct reimbursement of physician-based vaccination, offering free and preferably anonymous vaccination at community-based vaccination sites might improve uptake, especially among those targeted persons who rarely consult a physician.

Figure 1
Figure 1 Number of men who have sex with men reached by various information sources and vaccination status after meningococcal serogroup C vaccination recommendation, Berlin, November 2013-January 2014

Figure
Figure 2Number of prescribed doses of quadrivalent meningococcal serogroups ACWY conjugate vaccines according to quarter and federal state, Germany, 1 January 2012-30 June 2014

Figure 3
Figure 3Vaccination coverage for meningococcal serogroups C and ACWY vaccination as estimated by physicians at the time of the survey in participating practices for men who have sex with men without HIV-infection and HIV-infected patients

2
Number of prescribed doses of quadrivalent meningococcal serogroups ACWY conjugate vaccines according to quarter and federal state, Germany, 1 January 2012-30 June 2014 number of monovalent MenC or quadrivalent MenACWY conjugate vaccine doses prescribed within SHI from July 2013 to March 2014 was analysed based on data from Insight Health (http.//insight-health.de/).This database contains data from pharmaceutical data-processing centres on all directly reimbursed prescriptions for > 99% of persons insured by SHI (85% of the population) in Germany.However, data on recipients' age and sex are not available.SHI reimburses all prescriptions for vaccinations recommended by the German Standing Committee for Vaccination (STIKO).
Thus, prescriptions for meningococcal vaccination of people living with HIV (PLWHIV) were included in the Insight Health database, since vaccination was already recommended by STIKO for this group before the outbreak.However, meningococcal vaccination for non-HIV-infected, otherwise-healthy MSM living in Berlin as recommended by the Berlin authorities was not covered directly by SHI and thus not registered in this database.Rather, patients had to fill individual private prescriptions that SHI reimbursed on a voluntary basis.
During the outbreak, all LHA in Berlin were requested to elicit sexual orientation of IMD cases in men which is otherwise not routinely done.Ethical approval was not necessary since according to the Protection against Infection Act, local health authorities are authorised to request information on any risk factors relevant to outbreak control in patients and forward this information anonymously to the Robert Koch Institute.Possible outbreak-related cases were defined as follows: All MenC IMD in MSM aged 20-49 years, living in Berlin with illness onset from 1 July 2013 to 31 August 2014.

Table 1
Demographic and behavioural characteristics of Internet survey respondents resident in Berlin stratified according to awareness of vaccine recommendation and vaccine uptake, November 2013-January 2014 (n=1,429) a Men already vaccinated before the vaccination recommendation targeting men who have sex with men were excluded from this

analysis Invasive meningococcal disease cases in men who have sex with men after meningococcal C vaccine recommendation
ants in the first half of 2013 (four cases) to none in the second half of 2013, and none in the first half of 2014.From 2008 to 2012, annual MenC incidence in this age group in Berlin ranged from 0 to 0.79 (1-2 cases/year).The outbreak strain with fHbp 766 was not identified in any female cases.

Table 2
Results of two multivariable logistic regression models analysing factors associated with awareness of the vaccination recommendation and uptake of the MenC vaccine, Berlin, November 2013-January 2014 NA: not applicable; NS: not significant; OR: odds ratio; 95%CI: 95% confidence interval; Ref: reference group.

Table 3
Survey results of physicians of the working group on AIDS regarding the temporary implementation of meningococcal serogroup C vaccine recommendation for men who have sex with men in Berlin Berlin, Germany, February 2014 (n=30)