Optimizing Vaccination in Adult Patients With Liver Disease and Liver Transplantation

Short abstract

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-reading-rhee a video presentation of this article

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-interview-rhee an interview with the author

Abbreviations

ACIP

Advisory Committee on Immunization Practices

AST

American Society of Transplantation

CDC

Centers for Disease Control and Prevention

CLD

chronic liver disease

ESLD

end‐stage liver disease

FDA

US Food and Drug Administration

HAV

hepatitis A virus

HBV

hepatitis B virus

HPV

human papillomavirus

HZ

herpes zoster

IDSA

Infectious Diseases Society of America

IgG

immunoglobulin G

JEV

Japanese encephalitis virus

LD

liver disease

LT

liver transplantation

MenACWY

meningococcal ACWY

MMR

measles, mumps, and rubella

RZV

recombinant herpes zoster

SOT

solid organ transplantation

Tdap

tetanus, diphtheria, pertussis

VZV

varicella zoster virus

Key Take‐Home Points

• Clinicians should actively vaccinate patients with LD and following LT to reduce vaccine‐preventable illnesses.

• Early vaccination prior to progression of LD and prior to LT provides the best chance of optimal vaccine response.

• Vaccines are safe; however, live vaccines should not be provided in immunosuppressed patients with LD or after liver transplant (LT) because of risk for secondary disseminated disease. Transplant candidates should not receive live vaccines within 4 weeks of anticipated LT.

• Heplisav‐B and Shingrix are new inactivated recombinant vaccines with improved immunogenicity and better safety profiles. Gardasil‐9 can now be given to adults up to 45 years old.

• Travel‐related health counseling and vaccination in patients with LD and LT recipients is crucial and should be performed months prior to anticipated travel.

Patients with end‐stage liver disease (ESLD) and LT recipients remain at high risk for vaccine‐preventable infections in the pre‐ and post‐LT period.1, 2, 3 Despite higher risks, vaccine adherence remains low.4, 5, 6 Timing of vaccination remains crucial, because immunological responses are anticipated to be optimal in early liver disease (LD) and prior to LT7; therefore, every effort should be made to immunize prior to transplantation when possible. Guidelines recommend inactivated vaccines to be given 2 weeks and live vaccines 4 weeks prior to LT to maximize response and safely proceed with immunosuppression.8, 9 After LT, recommendations are to wait 3‐6 months when immunosuppression is at maintenance, except inactivated influenza vaccine, which can be given effectively 1 month after LT.9, 10 Vaccines should not be given during treatment for acute rejection, because increased immunosuppression may blunt vaccine response.9 Live vaccines should be avoided in immunosuppressed patients with LD and after LT.8, 9 Although there are theoretical risks of rejection with vaccination after solid organ transplantation (SOT; e.g., nonspecific immune activation or induction of T/B‐lymphocyte responses against alloantigens), there are no clinical data to support this concern.11, 12 Therefore, vaccination in patients with LD and LT far outweigh any potential risk and should be encouraged.

Routine vaccine schedules recommended for patients with LD and LT recipients are noted in Table 1, according to the Infectious Diseases Society of America (IDSA), American Society of Transplantation (AST) Infectious Diseases Community of Practice, and the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP).8, 9, 13 Regardless of prior vaccination, pretransplant serologies should be obtained for hepatitis A virus (HAV), hepatitis B virus (HBV), varicella zoster virus (VZV), and measles. A few vaccines are worth mentioning. Heplisav‐B (HepB‐CpG/HBsAg‐1018; Dynavax Technologies, Berkeley, CA, USA) is a yeast‐derived recombinant vaccine against HBV, which was approved by the US Food and Drug Administration (FDA) in November 2017. The superiority of HepB‐CpG/HBsAg‐1018 over existing standard dose (20 μg/mL) conventional recombinant vaccine was demonstrated in several phase 3 studies, with a seroprotection rate (defined as the proportion of adults with hepatitis B surface antibody titer ≥10 mIU/mL) of 90% to 95%, compared to 65% to 81%, respectively.14, 15, 16 Shingrix (GlaxoSmithKline, King of Prussia, PA, USA) is an inactivated adjuvanted recombinant subunit vaccine against herpes zoster (HZ) infection, which was approved by the FDA in October 2017 for use in adults ≥50 years old. In phase 3 studies, vaccine efficacy rate ranged from 96.6% to 97.9% for the prevention of HZ infection after a mean of 3.2 years, and high protection rates were sustained for adults ≥70 years old with a pooled vaccine efficacy rate of 91.3%.17, 18 Prior to the approval of Shingrix, only a live attenuated HZ vaccine was available that, in the Shingles Prevention Study, was associated with a 37.6% reduction in the incidence of HZ infection in subjects who were ≥70 years old.19 Although immunosuppressed patients were excluded from all of the aforementioned phase 3 studies, demonstrated efficacy of the new HBV and HZ vaccines in patients with expected decreased immunization response (e.g., diabetes mellitus, stem cell transplantation16, 20) shows promise for improved immunogenicity in patients with LD and LT recipients, as compared with older vaccine preparations. Lastly, in October 2018, the FDA approved the expanded use of Gardasil‐9 (Merck & Co., Inc., Kenilworth, NJ, USA), a recombinant vaccine against nine serotypes of human papillomavirus (HPV), to include men and women up to 45 years old.21 Studies on use of HPV vaccine in patients with LD or LT recipients are limited and suggest suboptimal serological response, with one study of 50 SOT recipients who received the quadrivalent HPV vaccine resulting in 52.6% to 68.4% serological response against the four serotypes.22 Nonetheless, SOT recipients remain at high risk for HPV‐associated malignancy, and all eligible adults up to 45 years old should undergo vaccination.23

Table 1.

Recommended Routine Vaccines in CLD/ESLD and LT8, 9, 13

Vaccine	Brand Name(s)	Clinical Description	CLD/ESLD	LT
Inactivated
HAV*	Havrix, Vaqta	HAV can be acquired by fecal‐oral transmission and can cause severe acute LD.	Yes. If HAV IgG antibody is not detected in the blood, two doses should be given at 0 and 6‐12 months. The CDC does not recommend checking postvaccination serology because response is generally good, there are no current standard booster recommendations, and tests may not be sensitive enough to detect low‐level protective antibodies.	Yes. Same as for CLD/ESLD. However, suboptimal responses to two doses of HAV vaccine may occur in transplant recipients.27 HAV IgG should be checked in high‐risk patients (i.e., travelers) with consideration of booster doses.9, 28
HBV*	Engerix‐B, Recombivax‐HB, Heplisav‐B (HepB‐CpG)	HBV is a blood‐borne pathogen that causes acute and/or chronic infection. There is a risk for hepatocellular carcinoma in chronic disease.	Yes. Indicated if HBV surface IgG antibody is not detected in the blood. Recommend Heplisav‐B at 0 and 1 month. Alternatives are Engerix‐B/Recombivax‐B 40 μg/mL at standard (0, 1, and 6) or accelerated (0, 1, 2, and 12 months) schedules.29, 30, 31 Check HBV surface IgG antibody at least 1 month after vaccination; if remains nonresponder, consider one‐time booster dose or repeat vaccination series. If isolated HBV core IgG antibody is detected, vaccine consideration depends on suspected reason.32	Yes. Same as for CLD/ESLD.
RZV	Shingrix	Shingles (HZ) disease is a reactivation of prior chickenpox (VZV) infection. Shingles can cause a painful local vesicular rash or disseminate.	Yes. Recommend if ≥50 years old, regardless of VZV serostatus or prior chickenpox or shingles disease.† Given as two‐dose series at 0 and 2‐6 months.	Yes. Same as for CLD/ESLD.
HPV	Gardasil‐9	The most feared complication of HPV infection is malignancy (genitourinary, anal, oropharyngeal), but it can also cause common and genital warts. Prognosis may be worse after LT because of immunosuppression.23	Yes. Recommend for adult men and women up to 45 years old. Given in three‐dose series at 0, 1‐2, and 6 months. Protects against nine serotypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58.	Yes. Same as for CLD/ESLD.
Influenza virus	Multiple	Both influenza A and B viruses can cause infection. Due to high mutation rates, seasonal vaccine will try to match a combination of the most likely circulating strains.	Yes. Should be received once yearly during the fall‐winter months.	Yes. Same as for CLD/ESLD.
Pneumococcal conjugate	Prevnar (PCV‐13)	Streptococcus pneumoniae is a bacteria that can cause pneumonia, meningitis, and other invasive disease. PCV13 protects against 13 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.	Yes. Should be received once as an adult, if not received during childhood primary series. Should be given ≥1 year after PPSV23, so preference is to give PCV13 first if both needed (see later).	Yes. Same as for ESLD/CLD.
Pneumococcal polysaccharide	Pneumovax (PPSV23)	Another pneumococcal vaccine. PPSV23 protects against 23 serotypes: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F.	Yes. Can receive up to three lifetime doses separated by ≥5 years. Up to 2 doses at <65 years old and a final dose at ≥65 years old. Give ≥8 weeks after PCV13 for optimal antibody response (see earlier).	Yes. Same as for CLD/ESLD.
Tetanus, diphtheria, pertussis (Td, Tdap)	Tenivac, Adacel, Boostrix	Tetanus is a nervous system infection that is caused by the bacteria Clostridium tetani. Diphtheria is caused by the bacteria Corynebacterium diphtheria and causes respiratory or other invasive disease. The bacteria Bordetella pertussis causes pertussis, otherwise known as “whooping cough”.	Yes. Tdap vaccine should be provided once, followed by Td booster every 10 years. If pertussis protection is desired, there is no minimum time interval between last Td and Tdap administration.	Yes. Same as for CLD/ESLD.
Live‡
Live Herpes Zoster (ZVL)	Zostavax	Another vaccine to prevent shingles disease (see earlier).	No. Recommend the newer inactivated vaccine (Shingrix) due to better immunogenicity.	No. Live vaccines are generally contraindicated after LT. Provide inactivated RZV vaccine (see earlier).
Influenza virus	FluMist	Another vaccine to prevent influenza infection (see earlier).	Maybe, for healthy adults ≤50 years old. However, unlikely to provide significant benefit over inactivated vaccine, with possible reduced comparative efficacy.33 Recommend inactivated vaccine for advanced LD. Consider timing if LT anticipated.	No. Live vaccines are generally contraindicated after LT. Provide inactivated influenza vaccine (see earlier).
MMR	M‐M‐R II	Measles, mumps and rubella are viral illnesses that may cause severe disease. The recent resurgence of measles and mumps highlights the need for immunization.	Yes. If MMR IgG antibodies are not detected, provide one dose.§ Do not recheck serology; may be unreliable to detect protection. Consider timing if LT anticipated.	No. Live vaccines are generally contraindicated after LT.
VZV	Varivax	Primary VZV infection causes chickenpox.	Yes. Recommend if ≤50 years old and VZV IgG antibody not detected; provide one dose and recheck serology at 4‐8 weeks. If antibody remains undetectable, provide second dose.‖ Note that CDC recommends two doses separated by ≥4 weeks with no follow‐up serology. Consider timing if LT anticipated.	No. Live vaccines are generally contraindicated after LT.

^aIndividual HAV and HBV vaccines may be substituted by Twinrix, the combination vaccine (contains Engerix‐B 20 μg/mL) that should be provided as a three‐dose series at 0, 1, and 6 months.

^bACIP recommendations.

^cRisks and benefits of live vaccines in patients with advanced LD and decompensated cirrhosis should be carefully considered. An equivalent inactivated vaccine is preferred when available. Live vaccines are contraindicated in immunosuppressed patients with LD.

^dACIP recommendations.

^eAST recommendations.

Patients with LD and LT recipients who wish to travel should be evaluated months in advance by a travel clinic. In addition to vaccination, extensive counseling should be provided on destination‐specific safe travel behaviors, food safety, minimizing exposure to endemic infections, prophylaxis for traveler’s diarrhea and malaria (and interactions with transplant rejection medications), insect protection, and posttravel care.24, 25 Routine vaccines should be updated, with particular focus on HAV, HBV, tetanus, diphtheria, pertussis (Tdap), and measles, mumps, and rubella (MMR) vaccines. Table 2 lists the most common travel vaccines that may be indicated in patients with LD and LT recipients, as recommended by the AST and ACIP.24 The CDC Yellow Book provides additional in‐depth information about travel health and infection prevention.26

Table 2.

Recommended Travel Vaccines in CLD/ESLD and LT

Vaccine*	Brand Name(s)	Clinical Description	CLD/ESLD	LT
Inactivated
JEV	Ixiaro	JEV is transmitted by mosquitos and is endemic to Asia and the Western Pacific. It causes neuroinvasive disease.	Yes, for travel to endemic areas. Two‐dose series at 0 and 28 days is recommended for long‐term travelers (≥1 month) or those with short‐term frequent or extensive rural travel. Consider booster dose if at continued risk and primary series received ≥1 year prior.	Yes. Same as for CLD/ESLD. A live attenuated vaccine used in Asia (SA 14‐14‐2) is contraindicated.
MenACWY†	Menactra, Menveo	Infection with the bacteria Neisseria meningitides can lead to meningitis and disseminated infection (meningococcemia) with shock. MenACWY protects against four serogroups: A, C, W, and Y.	Yes, for travel to high endemicity areas such as the meningitis belt of sub‐Saharan African and prior to Saudi Arabia travel for Hajj or Umrah. If primary series not received, two doses at 0 and ≥2 months with booster every 5 years if continued risk for exposure.	Yes. Same as for CLD/ESLD.
Inactivated poliovirus (IPV)	Ipol, multiple combination vaccines	Poliovirus causes neuroinvasive disease and is transmitted by fecal‐oral and pharyngeal route. Endemic in certain parts of Africa and Asia.	Yes, for travel to high‐risk areas. If primary series not received, three doses total at 0 and 1‐2 months, followed by 6‐12 months after second dose. Vaccinated adults are candidates for one lifetime booster if traveling to high‐risk region.	Yes. Same as for CLD/ESLD.
Rabies	Imovax, RabAvert	Rabies is a neuroinvasive infection caused by several neurotropic lyssaviruses. Prevalent in all continents, except Antarctica; transmitted by dogs and wild animals.	Yes, if potential risk for exposure. Pre‐exposure and postexposure vaccinations are given as a three‐dose (0, 7, and 21‐28 days) or a four‐dose (0, 3, 7, and 14 days) series, respectively. Pre‐exposure vaccination is indicated for long‐term travelers (≥1 month), planned animal contact, and/or remote from medical care. Booster doses every 6 months to 2 years may be recommended in certain high‐risk individuals at ongoing risk to maintain appropriate serum titers.	Yes. Same as for CLD/ESLD. In immunocompromised hosts, a fifth dose of postexposure vaccination is recommended at day 28.
Inactivated typhoid	Typhim Vi (intramuscular)	Typhoid (enteric) fever is caused by the bacteria Salmonella typhi and is transmitted by the fecal‐oral route. Fever and intestinal disease/diarrhea are most common, but extraintestinal disease can occur. Endemic worldwide but most prominent in low‐resource areas with poor sanitation.	Yes, for travel to rural areas of tropical countries. One‐dose injection, at least 2 weeks prior to travel to develop immunity. Booster dose every 2 years if ongoing risk.	Yes. Same as for CLD/ESLD.
Live‡
Cholera	Vaxchora (oral)	Infection with the bacteria Vibrio cholerae can lead to severe watery diarrhea and dehydration with electrolyte wasting.	Yes, for travel to areas of active cholera transmission. One oral dose should be received ≤10 days prior to potential exposure.	No. Live vaccines are generally contraindicated after LT.
Live typhoid	Vivotif (oral)	Another vaccine to prevent typhoid fever (see earlier).	Maybe, for travel to rural areas of tropical countries. Recommend inactivated vaccine if advanced LD, due to better safety profile and comparable efficacy.34 Four oral capsule doses on days 1, 3, 5, and 7. Last dose should be ≥1 week prior to travel to develop immunity. Booster dose every 5 years if ongoing risk. Consider timing if LT anticipated.	No. Live vaccines are generally contraindicated after LT. Provide inactivated typhoid vaccine (see earlier).
Yellow fever virus	YF‐Vax	Yellow fever virus is transmitted by mosquitos and is endemic to Africa and South America. It causes viral hemorrhagic fever and can lead to multiorgan failure.	Yes, if traveling to endemic areas. One dose provides lifelong immunity. Potential rare but serious adverse events include vaccine‐associated viscerotropic disease (YEL‐AVD) and neurological disease (YEL‐AND). Consider timing if LT is anticipated.	No. Live vaccines are generally contraindicated after LT. Travel to endemic regions with yellow fever should be avoided.

^aAnthrax, oral poliovirus, and smallpox vaccines are not readily available in United States.

^bAdditional indication for meningococcal vaccine includes asplenic patients, who should receive both MenACWY and MenB (Bexsero, Trumenba).

^cRisks and benefits of live vaccines in patients with advanced LD and decompensated cirrhosis should be carefully considered. An equivalent inactivated vaccine is preferred when available. Live vaccines are contraindicated in immunosuppressed patients with LD.

In conclusion, vaccine optimization in patients with LD and LT recipients is integral to the prevention of many communicable diseases. Vaccination should ideally occur in early LD and prior to LT, especially for live vaccines that are contraindicated after LT. Comprehensive counseling on travel health and vaccinations should be provided for travelers who are LT candidates and recipients.