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Background
Meningococcal disease is caused by gram- negative bacterium Neisseria meningitides, which is a
diplococcus and appears bean-shaped lying with flat surfaces adjacent to each other in a
polysaccharide capsule. The meningococci are usually found as commensal organisms in the upper
respiratory tract of about 10% of the population at any one time. Humans are the only natural
reservoir. Meningococcal disease generally manifests as acute illness but chronic course with a mean
duration of 6-8 weeks is also known (1). The disease spectrum includes meningitis, septicemia,
pneumonia, myocarditis, pericarditis, arthritis, and conjunctivitis, and occasionally may present as
shock referred to as Waterhouse-Friderichsen syndrome with high risk of mortality. In a study of 110
cases of invasive meningococcal disease during the outbreak in Meghalaya, meningitis was seen in
61.8% of cases, meningococcemia in 20 % and 18.2% had both. Non-blanching petechial rash was
seen only in 23.6% cases (2).
There are 1312 known serogroups (the previously defined 13th serogroup ‘D’ is now considered to be
an uncapsulated serogroup C variant) but 90% of the disease causing isolates belong to serogroups
A, B, C, YW (W-135 has been replaced with W as per new nomenclature), X and W-135.Y(3,4).
Emergence of Serogroup X over the last decade causing invasive disease is a cause of concern
globally particularly because of non-availability of vaccines for this serotgroup till date (5). The
burden of meningococcal disease is greatest in the African meningitis belt. In these areas, disease
occurs endemically in the dry season and also as epidemics every 7-14 years and iswas usually due to
serogroups A and W-135.. Post introduction of serogroup A conjugate vaccine since 2010 in the
meningitis belt, serogroup A disease almost disappeared while numbers of confirmed serogroup C
meningitis cases in the meningitis belt rose from 10 in 2013, to 48 in 2014, and to 1201 cases (to
Week 39) in 2015 (6). Disease outbreaks in Hajj Pilgrims have been attributed to A and W-135.
Disease in industrialized countries is primarily due to B, C and Y (27). There is lack of information of
serogroup responsible for endemic meningococcal disease in India. In one study from Post graduate
Institute of Medical Education and Research in Chandigarh, out of 12 isolates, eight were found to
be serogroup A and four were serogroup C (8). Sporadic cases of serogroup C (CMC, Vellore), B
(AIIMS and Chacha Nehru Bal Chikitsalaya, Delhi) and W (Thanjavur medical college, Thanjavur) are
also reported from various centers in India (9-12). However, Group A Meningococci is the cause of all
the major investigated Indian epidemics including Surat, Gujarat (1985-87), areas adjoining Delhi
(1966-1985) and (2004 - 2005)), and more recently in Meghalaya and Tripura in (2008 -2009). (The
most complete data available for this period is taken from an unpublished National Institute of
Communicable Disease Report 2009)) (13).
Global: In most countries, Neisseria meningitidis is recognized as a leading cause of meningitis and
fulminant septicaemia and a significant public health problem. Endemic disease mostly afflicts young
children; older children, adolescents and young adults mainly suffer during epidemics. In developing
countries the background incidence of meningococcal disease is 15-20 cases per 100,000 peoples
per year. When three or more cases of meningococcal disease occur in a 3-month period in the
same locality, amounting to at least 10 cases per 100,000 persons suffering from the disease, the
situation is referred as outbreak. However, in Sub Sahara Africa disease is hyper endemic due to
unknown reasons and is considered to have the highest annual incidence (10-25/100,000
population) of meningococcal disease in the world. In the African meningitis belt, the WHO
definition of a meningococcal epidemic is >100 cases/100 000 population/year. In endemic regions,
an incidence of >10 cases, 2–10 cases, and <2 cases per 100 000 population in a year characterizes
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high, moderate, and low endemicity, respectively (314). WHO defines ‘frequent epidemics’ as ≥1
epidemic over the past 20 years (15).
India: The data available on the background incidence of meningococcal disease in India are
suggestive of low incidence of meningococcal disease. Hence routine childhood vaccination with
meningococcal vaccine is unlikely to be a priority. As per the review by Sinclair et al (416), which is a
comprehensive study of epidemiology of Meningococcal disease in India, prevalence of meningitis is
1.5 -3.3% of all acute hospital admissions in children. N. meningitidis is the third most common cause
of bacterial meningitis in India in children less than 5 years of age and is responsible for an estimated
1.9% of all cases regardless of age (416). Prevalence of septicemia according to one study is 2.8% of
all hospital admissions.
As far as the epidemic disease is concerned, the outbreaks have occurred at a periodicity of 20 years.
Since 2005, there has been an increase in the number of meningococcal disease outbreaks reported
throughout India: New Delhi (2005–2009), Meghalaya (2008–2009) and Tripura (2009). Outbreaks
have been reported more in temperate northern than tropical southern regions of the country.
Large cities of North and coastal areas like Mumbai, Kolkata are being affected sparing the southern
and central regions. The important contributing factors in major outbreaks may be overcrowding or
vulnerability to importation of new strain or a suitable climatic condition.
The epidemic period coincides with dry season of November – March and the cases reduce with
onset of monsoon and again increase November onwards. The outbreaks occur when season is dry
and temperature is low. The seasonal cycle is similar to that seen in Africa where outbreaks peak in
hot dry season and subside during monsoon. The mechanism of this seasonal association is not
exactly known. This happens probably because during dry period there is damage to natural mucosal
barrier of the nasopharynx increasing the chance of invasion of viral infection. Most of the epidemics
in India are reported from the drier northern parts of the country than the more humid south is
supportive of the current view of seasonal effect of the disease.
The existence of endemic disease is recognized, but much of the epidemiological data that are
available are collected during outbreaks. Unlike Haemophilus influenzae type b (Hib), N. meningitidis
affects adults, as well as children. Endemic disease occurs primarily in infants and children with
highest attack rates in infants aged 3-12 months. The disease is found more in males than females.
During an epidemic condition, the disease is found in children; however, shift is noted from young
children to adolescents and young adults later. Overall carriage rates are lower in India than other
similar settings. High carriage rates are found in close household contacts which justifies
chemoprophylaxis. High carrier rates are also found among the military recruits.
During Inter-epidemic periods, confirmed case reporting (Form L from district/state level labs) of
Meningococcal meningitis is done under Integrated Disease Surveillance Programme (IDSP) of
National Centre for Disease Control, Delhi since 2004 (17).
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Central Bureau of Health Intelligence (CBHI) under Ministry of Health & Family Welfare, New Delhi
also reports the state wise number of meningococcal meningitis (ICD-10-CM Diagnosis Code A39.0)
cases in annual National Health Profile (NHP) publication. Cases reported in 2013, 2014 and 2015
were 3821, 4215 and 12002 respectively (19).
Severe meningococcal disease is associated with high case-fatality rates (5-15%) even where
adequate medical facilities are available and permanent disability occurs in about 19% survivors.
Chemoprophylactic measures are in general insufficient for the control of epidemics because
secondary cases comprise only 1-2% of all meningococcal cases.
Vaccines
TwoThree types of meningococcal vaccines have been developed but all are not available
everywhere (Table 1). They include:
These are either bivalent (A+C) or quadrivalent (A, C, W, Y, W135) and contain 50 μg of each of the
individual polysaccharides, available in lyophilized form, reconstituted with sterile water and stored
at 2 to 8°C. These “T cell independent” vaccines such as MPSV ACWY are not indicated for children
younger than 2 years of age, do not induce immunological memory and the response in children
younger than two years is poor.might induce immunological hypo responsiveness following
repeated doses.. Hence these are indicated for adults and children older than 2 years (only under
special circumstances A+ C vaccines can be used in children three months to two years of age).
Immunogenicity & efficacy: The antibody responses to each of the four polysaccharides in the
quadrivalent vaccine are serogroup-specific and independent. Protective antibody levels are usually
achieved within 10-14 days of vaccination. The serogroup A polysaccharide induces antibody in some
children as young as 3 months of age, although a response comparable with that occurring in adults
is not achieved until age 4-5 years. The serogroup C component is poorly immunogenic in children
less than 2 years. The serogroup A and C vaccines have good immunogenicity, with clinical efficacy
rates of 85% or higher among children 5 years of age or older and adults. Serogroup Y and W-135
polysaccharidesWpolysaccharides are safe and immunogenic in older children and adults; although
clinical protection has not been documented.
Duration of protection: In infants and young children aged < 5 years, measurable levels of antibodies
against serogroup A and C polysaccharides, as well as clinical efficacy, decrease substantially during
the first 3 years after a single dose of the vaccine administration. Antibody levels also decrease in
healthy adults, but antibodies are still detectable up to 10 years after immunization. Multiple doses
of serogroup A and C polysaccharides are known to cause immunologic hyporesponsiveness (impact
on clinical efficacy has not been demonstrated). Vaccines are safe and most common side effects are
local pain and redness at site of injection.
Currently twothree different types of meningococcal conjugate vaccines (MCVs) are licensed in
India. The first whichQuadrivalent vaccine Menactra® from Sanofi Pasteur is now readily available
for the last three years in private market also, is a. Another quadrivalent vaccine MenactraMenveo®
from Sanofi Pasteur,GSK and another a monovalent serogroup A vaccine from Serum Institute of
India (SII) are both licensed but yet not available in India (20).
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Quadrivalent Meningococcal Polysaccharide-protein Conjugate vaccine (MenACWY-D, Menactra®,
manufactured by Sanofi Pasteur)
Recent estimates of the effectiveness of MenACWY-D, the first licensed quadrivalent vaccine suggest
that within 3 to 4 years after vaccination, effectiveness is 80% to 85% (5, 6). There is higher level of
evidence for protection of children against meningococcal disease in children >12 months to <5
years of age than in individuals aged ≥5years (6).
In children between 9 months to 23 months of age, data on antibody persistence 3 years after a 2
dose series of MenACWY-D vaccine is demonstrated in study NCT00700713 (22). Best response was
seen for Seroroup A with 76.2% of participants achieving human Serum Bactericidal Antibody (hSBA)
Titers ≥ 1:4. Lowest response was seen for serogroup C (20.6%); however it is noteworthy that these
are results with hSBA which are usually lower than rSBA (rabbit Serum Bactericidal Antibody). In the
same study, a booster dose given 3 years after initial vaccination induced robust immune responses.
Antibody persistence data of single dose of MenACWY-D in age group 2 to 11 years is not yet
available.
In the age group 11 to 18 years, a 3 year follow-up study after a single dose on MenACWY-D vaccine
shows that 71% to 95% of participants had rSBA titers 128 or more for all 4 serogroups. A subset of
subjects from this study received a single booster dose 3 years after the initial vaccination. Rapid and
robust booster SBA responses were observed on day 8 after vaccination (23).
A case-control study (24) from USA provides vaccine effectiveness of MenACWY-D. The overall
estimate of vaccine effectiveness in adolescents vaccinated 0 through 6 years earlier was 69% (95%
confidence interval [CI] = 50%–81%).
It is associated with minor local side effects such as pain, and swelling. Guillain-Barré Syndrome
(GBS) was noted as a possible but unproven risk in some adolescents following immunization with
quadrivalent MCV. AsThe Harvard study (25) which involved 12.5 million adolescents who received
1.4 million doses of MenACYW-DT vaccine from 2005-2008 concluded that MCV4 vaccination was
not associated with increased GBS risk. However, as a precaution, people who have previously been
diagnosed with GBS should not receive this vaccine unless they are at increased risk of
meningococcal disease. Interference with PCV13 immune responses was noted when MenACWY-D
and PCV13 were administered simultaneously in patients with asplenia. Hence, CDC ACIP has now
recommended that for patients with asplenia, at least one month interval should be kept between
PCV13 and MenACWY-D, and PCV13 should be administered first (726).
A The phase III safety and immunogenicity open label non-randomized multi-centric phase III trial
(unpublished) of theMenACYW-DT in India was evaluated in age group 2 years through 55 years.
Subjects with protective SBA-BR titers ≥128 (1/dil) was over 94% for all age groups and serogroups,
except for serogroup C in children (80%). The vaccine has was safe and well tolerated in all age
groups (27).
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The phase III safety and immunogenicity of a 2 dose series of Menactra was also been conducted
amongstevaluated in Indian children, adolescents and adults, and aged 9-23 months (unpublished).
The preliminary results on thedata has shown that safety has been found to beand immunogenicity Formatted: Font: Calibri
are similar to US trials. However, no data on immunogenicity is available so far. those generated in Formatted: Font: Calibri
pivotal overseas studies (28, 29).
Between 2011 and 2014, 153 million people in age group 1-29 year were immunized in mass
vaccination campaigns in 12 of 26 countries in African meningitis belt (Benin, Burkina Faso,
Cameroon, Chad, Ethiopia, The Gambia, Ghana, Mali, Niger, Nigeria, Senegal, Sudan). This mass scale
rollout of MenAfriVac® campaign has dramatically reduced the incidence of Serogroup A disease in
the African meningitis belt. However in 2015, Serogroup C (which is previously not known to cause
disease in the belt) outbreaks started happening namely in Niger (1087 confirmed cases) and
Nigeria. As an emergency response, mass scale vaccination campaigns were started in Niger with
960,000 doses of ACW/ACYW polysaccharide vaccine and 200,000 doses of ACYW conjugate vaccine
in age range 2-15 years (6).
The single intramuscular dose induces functional antibody titres against meningococcal serogroup A
which are significantly higher and more persistent than those induced by a corresponding
polysaccharide vaccine (8-1030-32). The immune response seems to persist for a long time. The
vaccine has also got a very good safety profile. There is moderate level of evidence for protection of
children against Group A meningococcal disease in both children >12 months to <5 years, and in
individuals ≥5years old (1133). Furthermore, the vaccine has demonstrated a great effectiveness
when used in Africa in campaigns.
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MCV: Quadrivalent (serogroups A, Menactra, Lyophilized, 0.5ml by deep IM,
Meningococcal C, W135 & Y: contains 4 μg Sanofi Pasteur sterile revaccination after 3-
Conjugate each of A, C, Y and W-135 distilled 5 years in high-risk
vaccine polysaccharide conjugated water children and
to 48 μg of diphtheria adolescents
toxoid)
* Going to be available very soon in Indian market.* In India MenAfriVac is licensed for use in person aged 2-29
years (34)..
#
In infants aged 3 months to 2 years, MPSV may be given if risk for meningococcal disease is high, e.g.
outbreaks/ close household contacts: 2 doses 3 months apart.
Three characteristics of conjugate vaccines are believed to be important for establishing long-term
protection against a bacterial pathogen: memory response, herd immunity, and circulating antibody.
Recent data from the United Kingdom indicate that although vaccination primes the immune
system, the memory response after exposure might not be rapid enough to protect against
meningococcal disease. After initial priming with a serogroup C meningococcal conjugate vaccine, a
memory response after a booster dose was not measurable until 5–7 days later. The incubation
period for meningococcal disease usually is less than 3 days. In UK, to date no evidence of herd
immunity has been observed. Therefore, circulating bactericidal antibody is critical for protection
against meningococcal disease.
There is sufficient evidence to indicate that approximately 50% of persons vaccinated 5 years earlier
had bactericidal antibody levels protective against meningococcal disease. Therefore, more than
50% of persons immunized at age 11 or 12 years might not be protected when they are at higher risk
at ages 16 through 21 years. This is the reason why ACIP has now recommended revaccination with
MCV in individual previously vaccinated with either conjugated or polysaccharide vaccine who are at
increased risk for meningococcal disease. Those who are vaccinated at age greater than 7 years
should be vaccinated 5 years after their previous meningococcal vaccine and those vaccinated at
ages 2-6 years should be revaccinated 3 years after their previous meningococcal vaccine. Persons
who remain in one of these increase risk group indefinitely should continue to be revaccinated at 5
year interval.
The structural similarity of polysaccharide capsule of Serogroup B with the polysaccharide epitopes
of human nerve tissues may lead to immune tolerance and may trigger an autoimmune reaction if
used in the vaccine (35). Two MenB recombinant vaccines have recently been licensed globally
namely MenB-FHbp (Trumenba ®, Pfizer) and MenB-4C (Bexsero ®, GSK). However both are not
licensed to be used in India. Recently a phase II trial was conducted for immunogenicity and safety of
pentavalent serogroup ABCWY vaccine [consisting of recombinant proteins (rMenB) and outer
membrane vesicles (OMV), reconstituted with lyophilized MenACWY vaccine] by GSK. Overall, the
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immune responses against all vaccine serogroups were good 1 month after MenABCWY vaccination
and the immune responses in adolescents waned within 2 years of primary vaccination (36).
Recommendations for use
Individual use
The current epidemiology and burden of meningococcal diseases in India do not justify routine use
of meningococcal vaccines. Meningococcal vaccines are recommended only for certain high-risk
conditions and situations as enumerated below in children aged 2 years or more (3 months or older
if risk of meningococcal disease is high, e.g. outbreaks/ close household contact). Conjugate vaccines
are preferred over polysaccharide vaccines due to their potential for herd protection and their
increased immunogenicity, particularly in children <2 years of age.
IAP now recommends the use of MCVs in different categories as per following description:
Due to the limited efficacy of polysaccharide vaccines in children <2 years of age, conjugate vaccines
should be used for protection of those aged 12–24 months, particularly for Men A disease. Since
majority of documented outbreaks in India are caused by Men A, monovalent MCV, like PsA-TT
should be employed in mass vaccination.
i. Children with terminal complement component deficiencies: A two-dose primary series of MCV
administered 8–12 weeks apart is recommended for persons aged 24 months through 55 years with
persistent deficiencies of the late complement component pathway. A booster dose should be
administered every 5 years. Children who receive the primary series before their seventh birthday
should receive the first booster dose in 3 years and subsequent doses every 5 years.
ii. Children with functional/ anatomic asplenia/ hyposplenia (including sickle cell disease): Administer
2 primary doses of either MCV with at least 8 weeks between doses for individuals aged 24 months
through 55 years. Vaccination should ideally be started two weeks prior to splenectomy.
iii. Persons with Human Immunodeficiency Virus: Administer two doses at at least eight weeks
interval.
iv. Laboratory personnel and healthcare workers: who are exposed routinely to Neisseria
meningitides in solutions that may be aerosolized should be considered for vaccination. A single
dose of MCV is recommended. A booster dose should be administered every 5 years if exposure is
ongoing.
C. International Travellers
i. Students going for study abroad: Some institutions have policies requiring vaccination against
meningococcal disease as a condition of enrolment (mandatory in most universities in the USA).
Persons aged ≤21 years should have documentation of receipt of a MCV not more than 5 years
before enrolment. In US, ACIP recommends routine vaccination of all adolescents with single dose
of MCV4 at age 11–12 years, with a booster dose at age 16 years (available online at
http://www.cdc.gov/vaccines/pubs/acip-list.htm). For further details, follow the catch-up
recommendations for meningococcal vaccination of the destination country.
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ii. Hajj pilgrims: Vaccination in the 3 years before the date of travel is required for all travellers to
Mecca during the annual Hajj. The quadrivalent vaccine is preferred for Hajj pilgrims and
international travellers as it provides added protection against emerging W-135 and Y disease in
these areas. A single dose 0.5 ml IM is recommended in age group 2-55 years. Hajj pilgrims:
Vaccination with a single dose of tetravalent (ACYW) vaccine administered no less than 10 days
before arrival in Saudi Arabia is recommended by MOH (2016). Both polysaccharide and conjugate
vaccines are valid options. Conjugate vaccine certificate is valid for 8 years and if the vaccine type is
not indicated in the certificate, then it will be assumed that it is not the conjugate vaccine and the
validity of the certificate will be for 3 years (38).
iii. Travellers to countries in the African meningitis belt: A single dose of monovalent or quadrivalent
vaccine is recommended. Conjugate vaccine is preferred to polysaccharide vaccine. A booster dose
of MCV is needed if the last dose was administered 5 or more years previously.
Sporadic outbreaks of meningococcal disease have been recorded for last many decades in India.
These outbreaks, particularly the larger epidemics have almost universally been caused by serogroup
A meningococci (4). The committee believes that the new affordable serogroup A-containing
monovalent conjugate vaccine manufactured by SII should Serogroup A vaccins may have a critical
role in containing future epidemics. The Academy urges the Indian manufacturer to make this
vaccine , and should be made available in India. Howver, given the experience of mass vaccination
campaigns with monovalent serogroup A vaccine in the country also.African meningitis belt and the
following large outbreaks of serogroup C vaccine especially in Niger and Nigeria, the use of higher
valency conjugate vaccines may need to be considered for containing future epidemics (6). The
quadrivalent MenACWY-D should be employed in individuals having certain high-risk conditions and
situations and amongst international travellers (mentioned above).
Conjugated meningococcal vaccines are more expensive than polysaccharide vaccines. Based on
results on the cost effectiveness of use of MCVs in Australia, Canada, Netherlands, Portugal,
Switzerland and United Kingdom, it was found that one dose in the second year of life was more
cost-effective than a 3-dose infant schedule. The most cost-effective strategy was routine
vaccination of children at 12 months of age combined with a catch-up campaign for all children and
adolescents <18 years of age (1339). No studies on the cost-effectiveness of meningococcal
vaccination have yet been reported from India.
Decision to Vaccinate
If the attack rate of the meningococcal disease exceeds 10 cases per 100,000 persons then
vaccination of the population at risk should be considered keeping following factors in sight (2).
Completeness of case reporting and number of possible cases of meningococcal disease for
which bacteriologic confirmation or serogroup data are not available.
Occurrence of additional cases of meningococcal disease after recognition of a suspected
outbreak (e.g., if the outbreak occurred 2 months before and if no additional cases have
occurred, in which case vaccination might be unlikely to prevent additional cases of
meningococcal disease).
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Logistic and financial considerations. Because available vaccines are not effective against N.
meningitdis serogroup B, vaccination should not be given during serogroup B outbreaks.
Age consideration. Meningococcal disease outbreaks occur predominantly among persons
aged <30 years. If the calculated attack rate remains >10 cases/100,000 persons, then
vaccination should be considered for part or all of the population at risk.
In infants aged 3 months to 2 years, meningococcal conjugate vaccine is preferred.
If MCVs are not available, two doses of meningococcal polysachharide vaccine (MPSV) given
3 months apart may be administered if the risk for meningococcal disease is high, e.g.
outbreaks/ close household contacts.
Close child contacts of a patient with invasive meningococcal disease are at increased risk of
secondary disease. Most secondary cases occur within the first 72 hours after presentation
of the index case; risk of secondary disease decreases to near baseline by 10–14 days (5).
Meningococcal vaccines may be given to pregnant women during epidemics.
When there is an outbreak, immediate action is taken by the government. However, in remote areas
of the country, more time may be needed before remedial action can be expected. A rapid response
team typically composed of an epidemiologist, medical professionals and a microbiologist is
deployed to identify individuals exposed to meningococcal disease and to assist in the management
of those who are ill . If diagnostic facilities are not available locally, as is typical for remote areas of
the country, patient samples are sent to the NCDC for diagnostic testing . During the recent
outbreaks, microscopy, culture and latex agglutination tests were employed for diagnosis PCR was
also used to investigate the epidemic in New Delhi
Outbreak prevention and control actions in India: Following actions should be urgently taken after
confirmation of an outbreak:
Meningococcal vaccine
Recommended only for certain high risk group of children, during outbreaks, and
international travelers, including students going for study abroad and travelers to Hajj and
sub-Sahara Africa.
Conjugate vaccines are preferred over polysaccharide vaccines due to their potential for
herd protection and their increased immunogenicity, particularly in children <2 years of age.
As of today, quadrivalent conjugate and polysaccharide vaccines are recommended only for
children 2 years and above.
Monovalent group A conjugate vaccine, PsA–TT can be used in children above 1 year of age.
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Acknowledgements: Dr Sunil Gupta, Additional Director and Head Microbiology, NCDC,
Delhi, and Dr Himanshu Dubey, Sanofi Pasteur.
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