Meningococcemia primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

Primary prevention of meningococcemia includes vaccination and chemo prophylaxis. There are mainly 2 different types of vaccine namely polysacchride and conjugate vaccine. Chemoprophylaxis is mainly with rifampin, ceftriaxone, ciprofloxicin and azithromycin.

Primary Prevention

• Current vaccines have polysaccharides of groups A, C, Y, and W-135. No vaccine available presently for group B disease since the polysaccharide is not sufficiently immunogenic to produce a reliable antibody response in humans to be effective.
• There is a vaccine for the bacteria that cause meningococcal disease.
• Available vaccines do not cover all serogroups (“strains”) of Neisseria meningitidis bacteria.
• Meningococcal vaccines are not 100% effective. This means that even if you have been vaccinated, there is still a chance you can develop a meningococcal infection.

Who Needs to be Vaccinated ?

• First-year college student living in a residence hall
• Military recruit
• Damaged spleen or your spleen has been removed
• Terminal complement deficiency
• Microbiologist who is routinely exposed to Neisseria meningitidis (the causal pathogen)
• People traveling or residing in countries in which the disease is common.

Vaccine

Licensed Meningococcal Vaccine

There are two kinds of meningococcal vaccine in the U.S.:

• Meningococcal conjugate vaccine (MCV4) is the preferred vaccine for people 55 years of age and younger.
• Meningococcal polysaccharide vaccine (MPSV4) has been available since the 1970s. It is the only meningococcal vaccine licensed for people older than 55.

Formulation	Type	Age groups	Dose	Serogroups
MPSV4	Polysaccharide	≥2 yrs	Single dose	A, C, W, and Y
MenACWY-D	Conjugate	9–23 mos	2-dose series	A, C, W, and Y
MenACWY-CRM	Conjugate	2–10 yrs	Single dose	A, C, W, and Y
Hib-MenCY-TT	Conjugate	6 wks–18 mos	4-dose series	C and Y
Table adapted from CDC guidelines of Licensure of a Meningococcal Conjugate Vaccine for Children Aged 2 Through 10 Years and Updated Booster Dose Guidance for Adolescents and Other Persons at Increased Risk for Meningococcal Disease

Meningococcal Polysaccharide Vaccine (MPSV4)

• Both vaccines can prevent 4 types of meningococcal disease, including 2 of the 3 types most common in the United States and a type that causes epidemics in Africa.
• There are other types of meningococcal disease; the vaccines do not protect against these.The first meningococcal polysaccharide vaccine was licensed in the United States in 1974.
• The current quadrivalent A, C, Y, W-135 polysaccharide vaccine (Menomune, sanofi pasteur) was licensed in 1978.
• Each dose consists of 50 mcg of each of the four purified bacterial capsular polysaccharides. The vaccine contains lactose as a stabilizer.
• MPSV4 is administered by subcutaneous injection. The vaccine is available in single-dose and 10-dose vials. Fifty-dose vials are no longer available.
• Diluent for the single-dose vial is sterile water without preservative.
• Diluent for the 10-dose vial is sterile water with thimerosal added as a preservative. After reconstitution the vaccine is a clear colorless liquid.
• No vaccine is available in the United States for serogroup B.

Meningococcal Conjugate Vaccine (MCV4)

• Two meningococcal conjugate vaccines are licensed in the United States.
• Menactra (sanofi pasteur) was licensed in 2005.
• The vaccine contains N. meningiditis serogroups A, C, Y and W-135 capsular polysaccharide antigens conjugated to diphtheria toxoid protein.
• Each 0.5-mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 4 mcg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 mcg of diphtheria toxoid protein carrier.
• Menactra is approved for use in persons 9 months through 55 years of age.
• It is administered by intramuscular injection. Menactra is supplied as a liquid in a single-dose vial and does not contain a preservative or an adjuvant.Menveo (Novartis) was licensed in the United States in 2010.
• Menveo consists of two components: 10 µg of lyophilized meningococcal serogroup A capsular polysaccharide conjugated to CRM (MenA) and 5 µg each of capsular polysaccharide of serogroup C, Y, and W135 conjugated to CRM-197 in 0.5 mL of phosphate buffered saline, which is used to reconstitute the lyophilized MenA component before injection.
• Menveo is approved for use in persons 2 through 55 years of age. It is administered by [[intramuscular injection]. It does not contain a preservative or an adjuvant.

Immunogenicity and Vaccine Efficacy

Meningococcal Polysaccharide Vaccine

• The characteristics of MPSV4 are similar to other polysaccharide vaccines (e.g., pneumococcal polysaccharide).
• The vaccine is generally not effective in children younger than 18 months of age.
• The response to the vaccine is typical of a T-cell independent antigen, with an age-dependent response, and poor immunogenicity in children younger than 2 years of age.
• In addition, little boost in antibody titer occurs with repeated doses; the antibody which is produced is relatively low-affinity IgM, and “switching” from IgM to IgG production is poor.
• A protective level of antibody is usually achieved within 7–10 days of vaccination. Among infants and children younger than 5 years of age, the level of antibody against serogroup A and C polysaccharide decreases substantially during the first 3 years following a single dose of vaccine.
• In healthy adults, antibody levels also decrease, but antibodies are detectable as long as 10 years after vaccination.
• Although vaccine-induced protection likely persists in school-aged children and adults for at least 3 years, the efficacy of the group A vaccine in children younger than 5 years of age may decrease markedly within this period.
• In one study, efficacy declined from more than 90% to less than 10% 3 years after vaccination among children who were younger than 4 years of age when vaccinated.
• Efficacy was 67% among children who were older than 4 years of age at vaccination.

Meningococcal Conjugate Vaccine

• The approval of Menactra was based on studies that compared the serologic response to a single dose to the response of persons of similar age who received a single dose of meningococcal polysaccharide vaccine.
• In these studies a similar proportion of recipients achieved at least a fourfold rise in serum bactericidal antibody titer assay following MCV4 as those who received MPSV4.
• The proportion of recipients in each group that achieved a titer of 1:128 (the titer considered to predict protection) was more than 98% in both groups.
• The approval of Menveo was based on a comparison of serum bactericidal antibody responses to immunization with Menveo to those following immunization with Menactra.
• The response to Menveo was found to be non-inferior to the response to Menactra in all age groups that were studied (2 through 55 years).
• When MCV4 vaccine was licensed in 2005 it was believed that a single dose would provide protection for at least 10 years.
• Since that time serologic data have become available that show a significant decline in antibody 3 to 5 years after vaccination, although few cases among vaccinated persons have been reported.
• ACIP believes the serologic data are sufficiently compelling to recommend revaccination for persons at highest risk of meningococcal disease.
• Data indicate that the immune response to a single dose of meningococcal conjugate vaccine is not sufficient in persons with persistent complement component deficiency (e.g., C5--C9, properidin, factor H, or factor D deficiency) or asplenia.
• Persons with these conditions should receive a 2-dose primary series administered 2 months apart.

Schedule

Meningococcal Polysaccharide Vaccine

• Routine vaccination of civilians with MPSV4 is not recommended. Use of MPSV4 should be limited to persons older than 55 years of age, or when MCV4 is not available.

Meningococcal Conjugate Vaccine

• Two doses of MCV4 are recommended for adolescents 11 through 18 years of age: the first dose at 11 or 12 years of age, with a booster dose at age 16.
• Adolescents in this age group with HIV infection should get three doses: 2 doses 2 months apart at 11 or 12 years, plus a booster at age 16.
• If the first dose (or series) is given between 13 and 15 years of age, the booster should be given between 16 and 18. If the first dose (or series) is given after the 16th birthday, a booster is not needed.
• Healthy persons who receive their first routine dose of meningococcal conjugate vaccine at or after age 16 years do not need a booster dose.
• Routine vaccination of healthy persons who are not at increased risk for exposure to N. meningitidis is not recommended after age 21 years.
• A booster dose is not recommended for healthy persons 22 years of age or older even if the first dose was administered at 11 through 15 years of age.
• Persons with persistent complement component deficiency, and persons with functional or anatomic asplenia should receive a 2-dose primary series administered 2 months apart and a booster dose every 5 years.
• The minimum interval between MCV4 doses is 8 weeks. Although doses separated by 8 weeks can both be counted as valid it is preferable to use a longer interval between doses, 3 to 5 years if possible.
• MCV4 can be administered at the same visit as other indicated vaccines. All vaccines should be given at separate sites with separate syringes.
• Both MCV4 and MPSV4 are recommended for use in control of meningococcal outbreaks caused by vaccine-preventable serogroups (A, C, Y, and W-135).
• An outbreak is defined by the occurrence of at least three confirmed or probable primary cases of serogroup C meningococcal disease during a period of 3 months or less, with a resulting primary attack rate of 10 or more cases per 100,000 population.

Meningococcal Conjugate Vaccine Recommendations

Risk groups	Primary series	Booster dose
Persons aged 11 through 18 years	1 dose, preferably at age 11 or 12 years	At age 16 years if primary dose at age 11 or 12 years
Persons aged 11 through 18 years	1 dose, preferably at age 11 or 12 years	At age 16 through 18 years if primary dose at age 13 through 15 years
Persons aged 11 through 18 years	1 dose, preferably at age 11 or 12 years	No booster needed if primary dose on or after age 16 years
HIV-infected persons in this age group	2 doses, 2 months apart	At age 16 years if primary dose at age 11 or 12 years
HIV-infected persons in this age group	2 doses, 2 months apart	At age 16 through 18 years if primary dose at age 13 through 15 years
HIV-infected persons in this age group	2 doses, 2 months apart	No booster needed if primary dose on or after age 16 years
Persons aged 2 through 55 years with persistent complement component deficiency* or functional or anatomical asplenia	2 doses, 2 months apart	Every 5 years
Persons aged 2 through 55 years with persistent complement component deficiency* or functional or anatomical asplenia	2 doses, 2 months apart	At the earliest opportunity if a 1-dose primary series administered, then every 5 years
Persons aged 2 through 55 years with prolonged increased risk for exposure	1 dose	Persons aged 2 through 6 years:after 3 years
Persons aged 2 through 55 years with prolonged increased risk for exposure	1 dose	Persons aged 7 years or older:after 5 years
Table adapted from CDC guidelines of meningococcal conjugate vaccine recommendations by risk group by ACP (Table 2)

HIV Patients

• HIV infection is not currently considered to be an indication for MCV4 vaccination by itself.
• However, some persons with HIV infection should receive MCV4 for other indications, such as adolescents or international travel.
• Persons with HIV infection who are vaccinated with MCV4 should receive 2 doses at least 8 weeks apart. Persons with complement component deficiency, functional or anatomic asplenia or HIV infection who have already received 1 dose of MCV4 should receive a second dose at the earliest opportunity.

Children

• Children 9 through 23 months of age with persistent complement component deficiency, who are traveling to or residents of countries where meningococcal disease is hyperendemic or epidemic, and who are in a defined risk group during a community or institutional meningococcal outbreak should receive a 2-dose series of Menactra brand MCV4, 3 months apart.
• Because of their high risk for invasive pneumococcal disease, children with functional or anatomic asplenia should be vaccinated with MCV4 beginning at age 2 years to avoid interference with the immunologic response to the infant series of pneumococcal conjugate vaccine (PCV). The minimum interval between doses is 8 weeks.
• Persons who received the first dose of MCV or MPSV before 7 years of age and remain at increased risk for meningococcal disease should be revaccinated 3 years after the first dose. Persons who received a dose of MCV or MPSV at 7 years of age or older and remain at increased risk for meningococcal disease should be revaccinated 5 years after their previous dose.

Contraindication of Vaccination

• Anyone who has ever had a severe (life-threatening) allergic reaction to a previous dose of MCV4 or MPSV4 vaccine should not get another dose of either vaccine.
• Anyone who has a severe (life threatening) allergy to any vaccine component should not get the vaccine.
• Anyone who is moderately or severely ill at the time the shot is scheduled should probably wait until they recover. Ask your doctor. People with a mild illness can usually get the vaccine.
• Meningococcal vaccines may be given to pregnant women. MCV4 is a fairly new vaccine and has not been studied in pregnant women as much as MPSV4 has. It should be used only if clearly needed. The manufacturers of MCV4 maintain pregnancy registries for women who are vaccinated while pregnant.
• Breastfeeding and immunosuppression are not contraindications to vaccination.

Adverse reactions

General reactions

• Allergic reactions

• Hives
• Swelling of face and throat
• Difficulty breathing
• Palpitation
• Dizziness
• Weakness

• Fainting spells
• Seizure-like movements
• Fever

Reactions	MCV4	MPSV4
Local reactions for 1-2 days	4%-48%	11%-59%
Fever higher or equal to 100 degrees F	3%	5%
Systemic reactions (Headache,malaise, fatigue)	3%-60%	4%-62%
Table adapted from CDC guidelines of meningococcal conjugate vaccine recommendations by risk group by ACP (Table 2)

Meningococcal Polysaccharide Vaccine

• Adverse reactions to MPSV4 are generally mild.
• The most frequent are local reactions, such as pain and redness at the injection site.
• These reactions last for 1 or 2 days, and occur in up to 48% of recipients.
• Fever (100°– 103°F) within 7 days of vaccination is reported for up to 3% of recipients.
• Systemic reactions, such as headache and malaise, within 7 days of vaccination are reported for up to 60% of recipients. Fewer than 3% of recipients reported these systemic reactions as severe.

Meningococcal Conjugate Vaccine

• Reported adverse reactions following MCV4 are similar to those reported after MPSV4.
• The most frequent are local reactions, which are reported in up to 59% of recipients.
• Fever (100°– 103°F) within 7 days of vaccination is reported for up to 5% of recipients.
• Systemic reactions, such as headache and malaise are reported in up to 60% of recipients with 7 days of vaccination. Less than 3% of recipients reported these systemic reactions as severe.

Vaccine Handling

• Both MPSV4 and MCV4 should be shipped in insulated containers to prevent exposure to freezing temperature.
• Vaccine should be stored at refrigerator temperature (35°– 46°F, [2°– 8°C]). The vaccines must not be exposed to freezing temperature, and any vaccine exposed to freezing temperature should not be used.
• Single-dose vials of MPSV4 must be used within 30 minutes of reconstitution, and multidose vials must be discarded 10 days after reconstitution.
• The MenA (lyophilized) component of Menveo can only be reconstituted using the liquid C-Y-W135 component of Menveo. No other vaccine or diluents can be used for this purpose.
• The reconstituted vaccine should be used immediately, but may be held at or below 77°F (25°C) for up to 8 hours.
• If the liquid C-Y-W135 component of Menveo is administered without using it to reconstitute the lyophilized A component revaccination may not be needed.
• Serogroup A disease is rare in the U.S. so revaccination is not necessary if the person does not plan to travel outside the U.S.
• However, the person should be revaccinated with either a properly reconstituted dose of Menveo or with Menactra if international travel anticipated, especially travel to Africa.
• There is no minimum interval between the incomplete dose given in error and the repeat dose.

Chemoprophylaxis

• In the United States, the primary means for prevention of sporadic meningococcal disease is antimicrobial chemoprophylaxis of close contacts of infected persons.
• Close contacts include household members, child care center contacts, and anyone directly exposed to the patient’s oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management).
• For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index patient or for anyone seated directly next to an index patient on a prolonged flight (i.e., one lasting more than 8 hours).
• The attack rate for household contacts exposed to patients who have sporadic meningococcal disease was estimated to be four cases per 1,000 persons exposed, which is 500–800 times greater than the rate for the total population.
• In the United Kingdom, the attack rate among healthcare personnel exposed to patients with meningococcal disease was determined to be 25 times higher than among the general population.
• Because the rate of secondary disease for close contacts is highest immediately after onset of disease in the index patient, antimicrobial chemoprophylaxis should be administered as soon as possible, ideally less than 24 hours after identification of the index patient.
• Conversely, chemoprophylaxis administered more than 14 days after onset of illness in the index patient is probably of limited or no value.
• Oropharyngeal or nasopharyngeal cultures are not helpful in determining the need for chemoprophylaxis and might unnecessarily delay institution of this preventive measure.
• Rifampin, ciprofloxacin, and ceftriaxone are 90%–95% effective in reducing nasopharyngeal carriage of N. meningitidis and are all acceptable antimicrobial agents for chemoprophylaxis.
• Rifampin 600 mg PO q12h x 4 doses total or alternatively ciprofloxacin 500 mg PO x 1 in patients over 18 who cannot tolerate rifampin.

• Systemic antimicrobial therapy for meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins might not reliably eradicate nasopharyngeal carriage of N. meningitidis.
• If other agents have been used for treatment, the index patient should receive chemoprophylactic antibiotics for eradication of nasopharyngeal carriage before being discharged from the hospital.

Chemoprophylaxis

Drug	Age	Dose	Duration	Efficacy	Caution
Rifampin	<1 month	5mg/kg orally (Maximum 600mg, orally every 12 hour)	2 days	N/A	N/A
Rifampin	>/1 month	10 mg/kg (maximum 600 mg), orally, every 12 hout	2 days	90-95%	Can interfere with efficacy of oral contraceptives and some seizure prevention and anticoagulant medications; may stain soft contact lenses.Not recommended for pregnant women.
Ceftriaxone	<15 y	125 mg, intramuscular	Single dose	90-95%	To decrease pain at injection site, dilute with 1% lidocaine.
Ceftriaxone	>/15years	250 mg, intramuscularly	Single dose	90-95%	N/A
Ciprofloxacin	>/18years	500mg, orally	Single dose	90-95	Not recommended for persons <18 years of age. Not recommended for pregnant women.
Azithromycin	N/A	10 mg/kg(maximum 500 mg)	Single dose	90	Not recommended routinely. Equivalent to rifampin for eradication of Neisseria meningitidis from nasopharynx in one study.
Table adapted from CDC guidelines for recommended chemoprophylaxis regimens for high-risk contacts and persons with invasive meningococcal disease

Risk for travellers

The risk of meningococcal disease in travellers is generally low.

• Those travelling to industrialized countries may be exposed to sporadic cases, mostly of A, B or C. Outbreaks of meningococcal C disease occur in schools, colleges, military barracks and other places where large numbers of adolescents and young adults congregate.
• Travellers to the sub-Saharan meningitis belt may be exposed to outbreaks, most commonly of serogroup A and serogroup W-135 disease, with comparatively very high incidence rates during the dry season.
• Long-term travellers living in close contact with the indigenous population and pilgrims visiting Mecca for the hajj or umrah are at particular risk.

Vaccine

Polysaccharide vaccines

• Internationally marketed meningococcal polysaccharide vaccines are bivalent (A and C), trivalent (A, C and W-135) or tetravalent (A, C, Y and W-135).
• Following one single dose, in most cases subcutaneous, these vaccines provide excellent serogroup-specific protection lasting for 2-4 years in adults and children aged more than 2 years. Meningococcal polysaccharide vaccines are now often replaced by conjugate meningococcal vaccines.

Conjugate meningococcal vaccines

Conjugation of the meningococcal polysaccharide to a protein carrier induces a T-cell-dependent immune response characterized by increased immunogenicity among infants, prolonged duration of protection among older children and adults, and reduced nasopharyngeal carriage of meningococci.

Conjugate meningococcal vaccines are available as monovalent serogroup A and serogroup C vaccines, bivalent serogroups A and C vaccine and tetravalent serogroups A, C, Y and W-135 vaccine.

The conjugate vaccines are serogroup-specific and highly immunogenic (>90%). In contrast to group C polysaccharide vaccines, the group C conjugate vaccine elicits adequate antibody responses and immunological memory even in infants who are vaccinated at 2, 3 and 4 months of age.

• A conjugated serogroup A meningococcal vaccine, which was designed particularly for use in the African meningitis belt, is licensed for single-dose immunization of individuals aged 1–29 years.
• Three tetravalent conjugate vaccines against serogroups A, C, Y and W-135 meningococci are now licensed internationally. They differ in the conjugate carrier protein but all are administered ntramuscularly and show similar immunogenicity. These vaccines are licensed for single-dose immunization of individuals 2–55 years of age.
• Although tetravalent vaccines offer the widest range of protection, they do not protect against meningococci of serogroups B and X, which are common causes of meningococcal disease in some countries.

Required vaccinations

Saudi Arabia demands proof of recent meningococcal vaccination (with the tetravalent vaccine) as a visa requirement for pilgrims and guest workers.

Summary of vaccine data

Considerations
Type of vaccine	Polysaccharide vaccines that include 2-4 meningococcal serogroups: available as bivalent (A and C), trivalent (A, C and W-135) and tetravalent (A, C, Y and W-135) vaccines.
	Conjugate vaccines, available as monovalent (A or C), bivalent (A and C) and tetravalent (A, C, Y and W-135) vaccines.
Number of doses	For polysaccharide vaccines a single (mostly subcutaneous) dose to individuals aged 2 years or older. One booster may be required after 3-5 years.
	For conjugate vaccines primary series of 1-3 intramuscular doses with subsequent boosters. Schedule depends on choice of vaccine, as well as age and immunological status of the vaccinee.
Contraindications	Severe allergic reaction to vaccine components
Adverse reactions	Apart from transient local reactions, all meningococcal vaccines have an excellent safety record.
Before departure	Normally about 2 weeks, but may vary with vaccine and vaccinee.
Indications	Travellers from low-endemic regions visiting countries that are highly endemic for meningococcal disease. In the African meningitis belt, the risk of acquiring infection is greatest in the dry season and for people in close contact with the local population.