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Chapter 2 Preparing International Travelers

Vaccination & Immunoprophylaxis: General Recommendations

Andrew T. Kroger, Candice L. Robinson

Evaluation of people before travel should include a review and provision of routine vaccines recommended based on age and other individual characteristics. Additionally, some routine vaccines are recommended at earlier ages for inter­national travelers. For example, MMR (measles-mumps-rubella) vaccine and hepatitis A vaccine are recommended for infants aged 6–11 months who travel abroad. Recommendations for specific vaccines related to travel will depend on itinerary, duration of travel, and host factors. Vaccinations against diphtheria, tetanus, pertussis, measles, mumps, rubella, varicella, poliomyelitis, hepatitis A, hepatitis B, Haemophilus influenzae type b (Hib), rotavirus, human papillomavirus (HPV), and pneumococcal and meningococcal invasive disease are routinely administered in the United States, usually in childhood or adolescence. Influenza vaccine is routinely recommended for all people aged ≥6 months, each year. Herpes zoster (shingles) vaccine is recommended for adults aged ≥50 years.

If a person does not have a history of adequate protection against these diseases, immunizations appropriate to age and previous immunization status should be obtained, whether or not international travel is planned. A visit to a clinician for travel-related immunizations should be seen as an opportunity to bring an incompletely vaccinated person up-to-date on his or her routine vaccinations. For additional details on specific vaccines’ and toxoids’ recommendations, backgrounds, adverse reactions, precautions, and contraindications, refer to the respective ACIP recommendations (www.cdc.gov/vaccines/acip/index.html). For information on vaccinating travelers with altered immune function, see Chapter 5, Immunocompromised Travelers.

SPACING OF IMMUNOBIOLOGICS

Simultaneous Administration

With some exceptions (such as PCV13 and PPSV23, PCV13 and MenACWY-D [Menactra], and Menactra and DTaP), all commonly used vaccines can safely and effectively be given simultaneously (on the same day) at separate sites without impairing antibody responses or increasing rates of adverse reactions. This knowledge is particularly helpful for international travelers, for whom exposure to several infectious diseases might be imminent. Simultaneous administration of all indicated vaccines is encouraged for people who are the recommended age to receive these vaccines and for whom no contraindications exist. With the same exceptions as listed above for simultaneous vaccination, if not administered on the same day, an inactivated vaccine may be given at any time before or after a different inactivated vaccine or a live-virus vaccine. PCV13 and PPSV23 should be administered 8 weeks apart. PCV13 and Menactra should be administered 4 weeks apart in some high-risk groups. Menactra and DTaP should be administered 6 months apart in some high-risk groups.

The immune response to an injected or intranasal live-virus vaccine (such as MMR, varicella, or live attenuated influenza vaccines) might be impaired if administered within 28 days of another live-virus vaccine. Typically, the immune response is impaired only for the live-virus vaccine administered second. Whenever possible, injected or intranasal live-virus vaccines administered on different days should be given ≥28 days apart. If 2 injected or intranasal live-virus vaccines are not administered on the same day but <28 days apart, the second vaccine should be repeated in ≥28 days.

No evidence exists that inactivated vaccines interfere with the immune response to yellow fever vaccine. Therefore, inactivated vaccines can be administered either simultaneously or at any time before or after yellow fever vaccination. ACIP recommends that yellow fever vaccine be given at the same time as other live-virus vaccines.

Limited data suggest that coadministration of yellow fever vaccine with measles-rubella or MMR vaccines might decrease the immune response. One study involving the simultaneous administration of yellow fever and MMR vaccines and a second involving simultaneous administration of yellow fever and measles-rubella vaccines in children demonstrated a decreased immune response against all antigens except measles when the vaccines were given on the same day versus 30 days apart. Additional studies are needed to confirm these findings, but they suggest that, if possible, yellow fever and MMR should be given 30 days apart.

Additional data suggest that oral Ty21a typhoid vaccine, a live bacterial vaccine, can be administered simultaneously or at any interval before or after yellow fever vaccine. There are no data on the immune response to live attenuated oral cholera vaccine (Vaxchora) or nasally administered live attenuated influenza vaccine administered simultaneously with yellow fever vaccine. However, data from live attenuated influenza and MMR vaccines found no evidence of interference. If yellow fever vaccine and another injectable live-virus vaccine are not administered either simultaneously or ≥30 days apart, providers may consider measuring the patient’s neutralizing antibody response to vaccination before travel. Contact the state health department or the CDC Arboviral Disease Branch (970-221-6400) to discuss serologic testing.

No data are available on concomitant administration of the currently available formulation of oral cholera vaccine with other vaccines, including the enteric-coated oral typhoid vaccine. Based on expert opinion of how oral cholera vaccine buffer might interfere with the enteric-coated oral typhoid vaccine formulation, taking the first oral typhoid vaccine dose ≥8 hours after ingestion of oral cholera vaccine might decrease potential interference of the vaccine buffer with oral typhoid vaccine.

Measles and other live-virus vaccines may interfere with the response to tuberculin skin testing and the interferon-γ release assay. Tuberculin testing, if otherwise indicated, can be done either on the same day that live-virus vaccines are administered or 4–6 weeks later. Tuberculin skin testing is not a prerequisite for administration of any vaccine. Neither oral typhoid vaccine nor oral cholera vaccine have been associated with suppressing the response to tuberculosis testing.

Missed Doses and Boosters

In some cases, a scheduled dose of vaccine may not be given on time. If this occurs, the dose should be given at the next visit. However, travelers may forget to return to complete a series or for a booster at the specified time. Available data indicate that intervals between doses longer than those routinely recommended do not affect seroconversion rate or titer when the schedule is completed. Consequently, it is not necessary to restart the series or add doses of any vaccine because of an extended interval between doses. There are some exceptions to this rule. Some experts recommend repeating the series of oral typhoid vaccine if the 4-dose series is extended to more than 3 weeks. If an extended interval passes between doses of the preexposure rabies vaccine series, immune status should be assessed by serologic testing 7–14 days after the final dose in the series.

Antibody-Containing Blood Products

Antibody-containing blood products from the United States, such as immune globulin (IG) products, do not interfere with the immune response to yellow fever vaccine and are not believed to interfere with the response to live typhoid, live attenuated influenza, rotavirus, or zoster vaccines. When MMR and varicella vaccines are given shortly before, simultaneously with, or after an antibody-containing blood product, response to the vaccine can be diminished. The duration of inhibition of MMR and varicella vaccines is related to the dose of IG in the product. MMR and varicella vaccines either should be administered ≥2 weeks before receipt of a blood product or should be delayed 3–11 months after receipt of the blood product, depending on the dose and type of blood product (Table 2-04).

IG administration may become necessary for another indication after MMR or varicella vaccines have been given. In such a situation, the IG may interfere with the immune response to the MMR or varicella vaccines. Vaccine virus replication and stimulation of immunity usually occur 2–3 weeks after vaccination. If the interval between administration of 1 of these vaccines and the subsequent administration of an IG preparation is ≥14 days, the vaccine need not be readministered. If the interval is <14 days, the vaccine should be readministered after the interval shown in Table 2-04, unless serologic testing indicates that antibodies have been produced. Such testing should be performed after the interval shown in Table 2-04, to avoid detecting antibodies from the IG preparation.

When IG is given with the first dose of hepatitis A vaccine, the proportion of recipients who develop a protective level of antibody is not affected, but antibody concentrations are lower. Because the final concentrations of antibody are many times higher than those considered protective, this reduced immunogenicity is not expected to be clinically relevant. However, the effect of reduced antibody concentrations on long-term protection is unknown.

IG preparations interact minimally with other inactivated vaccines and toxoids. Other inacti­vated vaccines may be given simultaneously or at any time interval before or after an antibody-containing blood product is used. However, such vaccines should be administered at different sites from the IG.

Table 2-04. Recommended intervals between administration of antibody-containing products and measles-containing vaccine or varicella-containing vaccine1

INDICATION DOSE AND ROUTE RECOMMENDED INTERVAL BEFORE MEASLES OR VARICELLA VACCINATION
Blood Transfusion
Red blood cells (RBCs), washed 10 mL/kg (negligible IgG/kg) IV None
RBCs, adenine-saline added 10 mL/kg (10 mg IgG/kg) IV 3 months
Packed RBCs (hematocrit 65%)2 10 mL/kg (60 mg IgG/kg) IV 6 months
Whole blood (hematocrit 35%–50%)2 10 mL/kg (80–100 mg IgG/kg) IV 6 months
Plasma/platelet products 10 mL/kg (160 mg IgG/kg) IV 7 months
Botulism immune globulin, intravenous (human) 1.0 mL/kg (50 mg IgG/kg) IV 6 months
Cytomegalovirus prophylaxis (CMV IGIV) 150 mg/kg IV (maximum) 6 months
Hepatitis A (IG), duration of international travel
≤ 2-month stay 0.1 mL/kg (3.3 mg IgG/kg) IM 3 months
≥ 2-month stay 0.2 mL/kg (10 mg IgG/kg) IM 3 months
Hepatitis B prophylaxis (HBIG) 0.06 mL/kg (10 mg IgG/kg) IM 3 months
Intravenous immune globulin (IVIG)
Replacement therapy3 300-400 mg/kg IV3 8 months
Immune thrombocytopenic purpura (ITP) 400 mg/kg IV
800 mg/kg IV or 1 g/kg IV
8 months or
10 months4
Postexposure measles prophylaxis (for immunocompromised people) 400 mg/kg IV 8 months
Postexposure varicella prophylaxis5 400 mg/kg IV 8 months
Kawasaki disease 2 mg/kg IV 11 months
Measles prophylaxis (IG)
Immunocompetent contact 0.5 mL/kg (80 mg IgG/kg) IM 6 months
Monoclonal antibody to respiratory syncytial virus (RSV) F protein (Synagis [MedImmune])5 15 mg/kg IM None
Rabies prophylaxis (HRIG) 20 IU/kg (22 mg IgG/kg) IM 4 months
Tetanus (TIG) 250 units (10 mg IgG/kg) IM 3 months
Varicella zoster immune globulin4,5 125 units/10 kg (60–200 mg IgG/kg) IM (maximum 625 units) 5 months

Abbreviations: IG, immune globulin; IM, intramuscular; IV, intravenous.
1Adapted from Table 3.5, Kroger AT, Duchin J, Vázquez M. General best practice guidelines for immunization. Best practices guidance of the Advisory Committee on Immunization Practices (ACIP). Atlanta, GA: CDC [cited 2018 Jan 18]. Available from: www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. This table is not intended for determining the correct indications and dosage for the use of IG preparations. Unvaccinated people may not be fully protected against measles during the entire recommended interval, and additional doses of IG or measles vaccine may be indicated after measles exposure. Concentrations of measles antibody in an IG preparation can vary by manufacturer’s lot. For example, more than a 4-fold variation in the amount of measles antibody titers has been demonstrated in different IG preparations. Rates of antibody clearance after receipt of an IG preparation can also vary. Recommended intervals are extrapolated from an estimated half-life of 30 days for passively acquired antibody and an observed interference with the immune response to measles vaccine for 5 months after a dose of 80 mg IgG/kg (Source: Mason W, Takahashi M, Schneider T. Persisting passively acquired measles antibody following gamma globulin therapy for Kawasaki disease and response to live virus vaccination [abstract 311]. Presented at the 32nd meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, California, October 1992). Does not include zoster vaccine. Zoster vaccine may be given with antibody-containing products.
2Assumes a serum IgG concentration of 16 mg/mL.
3Measles vaccination is recommended for children with mild or moderate immunosuppression from HIV infections and varicella vaccination may be considered for children with mild or moderate immunosuppression from HIV infections, but both are contraindicated for people with severe immunosuppression from HIV, with any other immunosuppressive disorder, or on immunosuppressive medications.
4Recommendation adapted from Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190–207.
5If varicella zoster immune globulin is not available, IVIG can be used. The recommendation for use of IVIG is based on best judgment of experts and is supported by reports comparing varicella IgG titers measured in both IVIG and varicella zoster immune globulin preparations and patients given IVIG and varicella zoster immune globulin. Although licensed IVIG preparations contain antivaricella antibodies, the titer of any specific lot of IVIG is uncertain, because IVIG is not tested routinely for antivaricella antibodies. No clinical data demonstrating effectiveness of IVIG for postexposure prophylaxis of varicella are available. The recommended IVIG dose for postexposure prophylaxis of varicella is 1 dose of 400 mg/kg, intravenously (see http://redbook.solutions.aap.org/chapter.aspx?sectionid=88187270&bookid=1484).
6Contains only antibody to respiratory syncytial virus.

 

VACCINATING PEOPLE WITH ACUTE ILLNESSES

Every opportunity should be taken to provide needed vaccinations. The decision to delay vaccination because of a current or recent acute illness depends on the severity of the symptoms and their cause. Although a moderate or severe acute illness is sufficient reason to postpone vaccination, minor illnesses (such as diarrhea, mild upper respiratory infection with or without low-grade fever, or other low-grade febrile illness) are not contraindications to vaccination.

Antimicrobial therapy is not a contraindication to vaccination, with several exceptions:

  • Antibiotics may interfere with the response to oral typhoid vaccine and oral cholera vaccine.
  • Antiviral agents active against herpes viruses (such as acyclovir) may interfere with the response to varicella-containing vaccines.
  • Antiviral agents active against influenza virus (such as zanamivir and oseltamivir) may interfere with the response to live attenuated influenza vaccine.

VACCINATION SCHEDULING FOR SELECTED TRAVEL VACCINES

Table 2-05 lists the minimum age and minimum interval between doses for vaccines routinely recommended in the United States.

Table 2-05. Recommended and minimum ages and intervals vaccine doses1,2

VACCINE AND DOSE NUMBER RECOMMENDED AGE FOR THIS DOSE MINIMUM AGE FOR THIS DOSE MINIMUM INTERVAL TO NEXT DOSE3
Japanese encephalitis, Vero cell (Ixiaro)-14 2 months–17 years
18–65 years
≥2 months
≥18 years
28 days
7 days
Ixiaro-2 2 months–17 years: 28 days after dose 1
18–65 years: 7 days after dose 1
28 days after dose 1
7 days after dose 1
NA
Live cholera vaccine (Vaxchora)
Rabies-1 (preexposure)
18–64 years
See footnote 6
18 years NA
Rabies-2 7 days after dose 1 7 days after dose 1 14 days
Rabies-3 21 days after dose 1 21 days after dose 1 NA
Typhoid, inactivated (ViCPS) ≥2 years ≥2 years NA
Typhoid, live attenuated (Ty21a) ≥6 years ≥6 years See footnote 6
Yellow Fever >9 months7 >9 months7 10 years

1Adapted from Table 1, CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011 Jan 28;60(RR-2):1–61.
2Combination vaccines are available. Use of licensed combination vaccines is generally preferred over separate injections of their equivalent component vaccines (CDC. Combination vaccines for childhood immunization. MMWR Recomm Rep. 1999 May 14;48[RR-5]:1–14.). When administering combination vaccines, the minimum age for administration is the oldest age for any of the individual components (exception: the minimum age for the first dose of MenHibrix is 6 weeks); the minimum interval between doses is equal to the largest interval of any of the individual components.
3 See www.cdc.gov/vaccines/schedules for recommended revaccination (booster) schedules.
4 Ixiaro is approved by the Food and Drug Administration for people aged ≥2 months.
5There is no minimum age for preexposure immunization for rabies (CDC. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008 May 23;57[RR-3]:1–28).
6Oral typhoid vaccine is recommended to be administered 1 hour before a meal with a cold or lukewarm drink (temperature not to exceed body temperature—98.6°F [37°C]) on alternate days, for a total of 4 doses.
7Yellow fever vaccine may be administered to children aged <9 months in certain situations (CDC. Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR Recomm Rep. 2010 Jul 30;59[RR-7]:1–27.).
pregnant women, preferably at 27–36 weeks’ gestation, regardless of history of previous Tdap vaccination.

ALLERGY TO VACCINE COMPONENTS

Vaccine components can cause allergic reac­tions in some recipients. These reactions can be local or systemic and can include anaphylaxis or anaphylacticlike responses. The vaccine components responsible can include the vaccine antigen, animal proteins, antibiotics, preservatives (such as thimerosal), or stabilizers (such as gelatin). The most common animal protein allergen is egg protein in vaccines prepared by using embryonated chicken eggs (influenza and yellow fever vaccines). People with a history of egg allergy who have experienced only hives after exposure to egg should receive influenza vaccine. Any licensed inactivated influenza vaccine that is otherwise appropriate for the recipient’s age and health status may be used.

People who report having had reactions to egg involving symptoms other than hives, such as angioedema, respiratory distress, lightheadedness, or recurrent emesis, or who required epinephrine or another emergency medical intervention, may similarly receive any licensed inactivated influenza vaccine that is otherwise appropriate for the recipient’s age and health status. If a person has a severe egg sensitivity or has a positive skin test to yellow fever vaccine but the vaccination is recommended because of their travel destination–specific risk, desensitization can be performed under direct supervision of a physician experienced in the management of anaphylaxis. In such circumstances, both yellow fever and influenza vaccines should be administered in an inpatient or outpatient medical setting. Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. A previous severe allergic reaction to any vaccine, regardless of the component suspected of being responsible for the reaction, is a contraindication to future receipt of the vaccine.

Some vaccines contain a preservative or trace amounts of antibiotics to which people might be allergic. Providers administering the vaccines should carefully review the prescribing information before deciding if the rare person with such an allergy should receive the vaccine. No recommended vaccine contains penicillin or penicillin derivatives. Some vaccines (MMR vaccine, inactivated polio vaccine [IPV], hepatitis A vaccine, some hepatitis B vaccines, some influenza vaccines, rabies vaccine, varicella vaccine, and smallpox vaccine) contain trace amounts of neomycin or other antibiotics; the amount is less than would normally be used for the skin test to determine hypersensitivity. However, people who have experienced anaphylactic reactions to this antibiotic generally should not receive these vaccines. Most often, neomycin allergy is a contact dermatitis— a manifestation of a delayed-type (cell-mediated) immune response rather than anaphylaxis. A history of delayed-type reactions to neomycin is not a contraindication to receiving these vaccines.

Thimerosal, an organic mercurial compound in use since the 1930s, has been added to certain immunobiologic products as a preservative. Thimerosal is present at preservative concen­trations in multidose vials of some brands of vaccine. Receiving thimerosal-containing vaccines has been postulated to lead to induction of allergy. However, there is limited scientific evidence for this assertion. Allergy to thimerosal usually consists of local delayed-type hypersensitivity reactions. Thimerosal elicits positive delayed-type hypersensitivity patch tests in 1%–18% of people tested, but these tests have limited or no clinical relevance. Most people do not experience reactions to thimerosal administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. A localized or delayed-type hypersensitivity reaction to thimerosal is not a contraindication to receipt of a vaccine that contains thimerosal.

Since mid-2001, vaccines routinely recom­mended for infants have been manufactured without thimerosal as a preservative. Vaccines that still contain thimerosal as a preservative include some influenza vaccines, DT, and 1 Td vaccine. Additional information about thimerosal and the thimerosal content of vaccines is available on the FDA website (www.fda.gov/cber/vaccine/thimerosal.htm).

REPORTING ADVERSE EVENTS AFTER IMMUNIZATION

Modern vaccines are extremely safe and effective. Benefits and risks are associated with the use of all immunobiologics—no vaccine is completely effective or completely safe for all recipients. Adverse events after immunization have been reported with all vaccines, ranging from frequent, minor, local reactions to extremely rare, severe, systemic illness, such as that associated with yellow fever vaccine. Adverse events following specific vaccines and toxoids are discussed in detail in each ACIP statement. In the United States, clinicians are required by law to report selected adverse events occurring after vaccination with any vaccine in the recommended childhood series. In addition, CDC strongly recommends that all vaccine adverse events be reported to the Vaccine Adverse Event Reporting System (VAERS), even if a causal relation to vaccination is not certain. VAERS reporting forms and information are available electronically at www.vaers.hhs.gov, or they may be requested by telephone: 800-822-7967 (toll-free). Clinicians are encouraged to report electronically at https://vaers.hhs.gov/esub/step1.

INJECTION ROUTE AND INJECTION SITE

Injectable vaccines are administered by intramuscular, intradermal, and subcutaneous routes. The method of administration of injectable vaccines depends in part on the presence of an adjuvant in some vaccines. The term adjuvant refers to a vaccine component distinct from the antigen, which enhances the immune response to the antigen. Vaccines containing an adjuvant (DTaP, DT, HPV, RZV, Td, Tdap, pneumococcal conjugate, Hib, hepatitis A, hepatitis B) should be injected into a muscle mass, because administration subcutaneously or intradermally can cause local irritation, induration, skin discoloration, inflammation, and granuloma formation. Detailed discussion and recommendations about vaccination of people with bleeding disorders or receiving anticoagulant therapy are available in the ACIP general best practices guidelines for immunization.

Routes of administration are recommended by the manufacturer for each immunobiologic. Deviation from the recommended route of administration may reduce vaccine efficacy or increase local adverse reactions. Detailed recommendations on the route and site for all vaccines have been published in ACIP recommendations; a compiled list of these publications is available on the CDC website at www.cdc.gov/vaccines/hcp/acip-recs (also see Appendix B).

BIBLIOGRAPHY

  1. CDC. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008 May 23;57(RR-3):1–28.
  2. CDC. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2012 Jun 29;61(25):468–70.
  3. Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013 Mar 22;62(2):1–28.
  4. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices— United States, 2017–2018 influenza season. MMWR Recomm Rep. 2017;66(RR-2):1–22.
  5. Kobayashi M, Bennett NM, Gierke R, Almendares O, Moore MR, Whitney CG, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015 Sep 4;64(64):944–7.
  6. Kroger AT, Duchin J, Vázquez M. General best practice guidelines for immunization. Best practices guidance of the Advisory Committee on Immunization Practices (ACIP). Atlanta, GA: CDC [cited 2018 Jan 18]. Available from: www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf.
  7. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS, CDC. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013 Jun 14;62(RR-04):1–34.
  8. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190–207.
  9. Shimabukuro TT, Nguyen M, Martin D, DeStefano F. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015 Aug 26;33(36):4398–405.
  10. Staples JE, Gershman M, Fischer M, CDC. Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Jul 30;59(RR-7):1–27.
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