Practical review of immunizations in adult patients with cancer

Abstract

Compared with the general population, patients with cancer in general are more susceptible to vaccine-preventable infections, either by an increased risk due to the malignancy itself or immunosuppressive treatment. The goal of immunizations in these patients is therefore to provide protection against these infections, and to decrease the number of vulnerable patients who can disseminate these organisms. The proper timing of immunization with cancer treatment is key to achieving better vaccine protection. As the oncology field continues to advance, leading to better quality of life and longer survival, immunization and other aspects of preventive medicine ought to move to the frontline in the care of these patients. Herein, we review the vaccines most clinically relevant to patients with cancer, as well as special cases including vaccines after splenectomy, travel immunization and recommendations for family members.

Keywords:

• cancer
• immunization
• infection
• prevention
• vaccine

General Recommendations

Treatment regimens for oncological diseases have evolved dramatically over the past years and continue to change with the advent of new medications. Clinicians have become increasingly aware of the risk of infection associated with the malignancy itself and/or immunosuppressive therapies, including higher risk for pneumococcus, influenza infection and hepatitis B among others.^1-4 In general, adults with oncological diseases should be advised to adhere to standard recommended immunization schedules, but they should avoid live vaccines while on immunosuppressive therapy. Types of immunizations are review in Table 1.

Table 1. Mechanisms for acquiring immunity from vaccines

Type of Immunization	Principle of Action	Examples	Comments
Non-replicating vaccines	Based on toxoid, protein subunits, bacterial, antigens, or immunogenic proteins obtained with recombinant, technology.	Tetanus, diphtheria, pertussis, poliomyelitis, hepatitis B, influenza, Haemophilus influenza, pneumococcus, meningococcus	Usually requires 3–5 doses; antibody titers diminishes with time
Replicating live attenuated vaccines	Produced by disabling the virulent properties of a disease-producing virus or bacterium	Measles-mumps-rubella, varicella, intranasal influenza, yellow fever, oral polio, oral typhoid	Severe reactions are possible; transmission of live pathogen may occur; most provide immunity with 1 dose
Passive immunization	Antibodies are infused to provide short-term protection	Varicella Immunoglobulin, hepatitis B immunoglobulin	Protection diminishes after weeks or months

The aim of this manuscript is to review the current evidence and to elucidate the practical aspects of vaccination in patients with oncological condition (excluding stem cell transplant recipients) and family members, providing useful immunization recommendations for primary care providers, infectious diseases practitioners and oncologists.

Inactivated vaccines

In general, inactivated vaccines should be given at least 2 weeks before the initiation of chemotherapy or other immunosuppressive therapy to maximize the immune response. Vaccination during chemotherapy or radiation therapy should be avoided because antibody responses are suboptimal. However, vaccination with inactivated vaccines during this period is not harmful and appears to provide sero-protection against some pathogens in some patients.⁵

Live attenuated vaccines

Live attenuated vaccines should be administered at least 4 weeks prior to immunosuppressive therapy.^5,6 The recommendations by the Centers for Disease Control and the Infectious Diseases Society of America (IDSA), is that vaccination after chemotherapy should not occur until at least 3 months after the discontinuation of the immunosuppressive therapy, except for patients receiving regimens that include anti–B-cell antibodies, in which case, vaccination should be delayed for at least 6 months after treatment.⁷ However, the treating physician should carefully consider the use of live attenuated vaccines, as some other chemotherapy agents would cause immunosuppression for over 3 months.^8,9

Vaccine efficacy

Vaccine efficacy, which is based on the reduction of infection rates in a community, can be very difficult to assess in oncological patients owing to a low incidence of infection (e.g., tetanus) or the seasonality of infection (e.g., influenza).¹⁰ Most data on vaccination in cancer patients are from underpowered studies that include patients with different cancers and chemotherapy treatments and that use diverse definitions of vaccine response.⁶ Classically, vaccine response is measured by assessing pre- and post-vaccination antibody titers (Immunoglobulin G), which should be performed by the same laboratory. The precise methods used to measure vaccine response vary depending on the vaccine as well as the antibody titer cut-off level used to indicate protection.¹¹

Inactivated Vaccines

Influenza vaccine

Cancer patients are known to be at great risk for morbidity secondary to influenza infection, including bacterial pneumonia and respiratory insufficiency,^12-14 and mortality, the rate of which ranges from 9% to 33% depending on the underlying malignancy.¹³ Therefore, influenza vaccination should be offered to all cancer patients except those receiving intensive chemotherapy (e.g., acute leukemia patients receiving induction or consolidation therapy) or anti-B-cell antibodies. Family members and other close contacts of patients with cancer should also be vaccinated against influenza.⁵ The recommended influenza vaccine in patients with cancer is the intramuscular inactivated vaccine. Intranasal administered live attenuated influenza vaccine (LAIV) is currently not recommended for patients with cancer as there is scarce data on safety. To our knowledge, only one study by Carr et al.¹⁵ has evaluated the safety of LAIV in non-neutropenic children with cancer who were classify as mild to moderately immunocompromised, describing the live vaccine to be safe and immunogenic. However as there is a safe non-live vaccine alternative, the current recommendations including ours are to avoid LAIV.

The timing of influenza vaccination in relation to chemotherapy helps to determine the vaccine's serological response. Influenza is a seasonal disease, and waiting to give the vaccine until a few months after chemotherapy may not be an option in some clinical circumstances. For patients who are undergoing or who are about to undergo chemotherapy, the best option may be to administer the vaccine 2 weeks before or 2 weeks after chemotherapy or to administer the vaccine between chemotherapy cycles, and trying to avoid giving the vaccine when the patients' white blood cell counts are at their nadir.¹⁶ The concurrent administration of granulocyte-macrophage colony-stimulating factor at the time of vaccination is not recommended, as it was not found to have a positive effect on the serological response to influenza vaccination.¹⁷

The efficacy of the influenza vaccine is typically assessed by measuring hemagglutinin antibody titers. A serum antibody titer of 40 or a 4-fold increase in the hemagglutinin titer is normally considered protective in healthy individuals.¹⁸ Using these parameters, several studies have shown that the vaccine response varies depending on the cancer type. For instance, patients with breast cancer^19,20 or lung cancer²¹ have mean vaccine response rates of 66% and 78%, respectively, which are similar to that of the general population. On the other hand, patients with hematological malignancies such as multiple myeloma have much lower vaccine response rates, which range from 19% to 27%.^22,23

To improve the immunogenicity of influenza vaccination, researchers have developed new methods of delivering the vaccine, although none has become the standard of care. The first such method is the use of a high-dose vaccine. In one study, Safdar et al. compared adult non-Hodgkin lymphoma patients who received a 45-mcg-influenza vaccine with those who received a 135-mcg vaccine and reported response rates of 40% and 60%, respectively; however, the study population was too small to determine whether this difference was statistically significant.²⁴ The authors also reported no difference in adverse reactions between the regular-dose and high-dose groups,²⁴ although others have reported that the high-dose vaccine is associated with increased local pain and myalgia.²⁵ The second novel method of delivering the influenza vaccine is the 2-shot influenza vaccine. Lo et al. found that the vaccine response rate of patients who received 2 doses (71%) was significantly higher than that of patients who received one dose (42%; p = 0.006).²⁶ In another study, Cheng et al. reported sero-protection rates of 58.3% after one dose and 100% after 2 doses among children who had completed chemotherapy or who were receiving maintenance chemotherapy.²⁷ One of the caveats of the 2-dose vaccination strategy is the compliance rate, which for healthy children is 9.1%–60.1% depending on age; adolescents tend to have lower compliance rates.^28,29

Several aspects, including the seasonality and variation of influenza strains as well as difficulty achieving adequate statistical power to identify significant differences between groups, limit researchers' ability to accurately assess the effectiveness of the influenza vaccine. However, a recent meta-analysis described that the rates of lower respiratory disease, hospitalization, and mortality among cancer patients who received the influenza vaccine were significantly lower than those among cancer patients who did not.³⁰ Given this favorable risk-benefit profile, physicians should make every effort to further increase the rate of influenza vaccination.

Pneumococcal vaccine

Streptococcus pneumoniae infection may have serious implications in patients with cancer including a high risk for invasive pneumococcal disease especially for patients with multiple myeloma, lung cancer, chronic lymphocytic leukemia, and lymphoma.^31,32 However, owing to the low incidence of pneumococcal infection among cancer patients, documenting the effect of the pneumococcal vaccine in terms of reducing the risk for invasive pneumococcal disease is very difficult. Studies have suggested that the pneumococcal vaccine reduces the burden of invasive pneumococcal disease and non-bacteremic pneumococcal pneumonia in both healthy adults and HIV-positive patients.^33,34 Therefore, as the risk for invasive pneumococcal disease is higher in patients with oncological diseases, pneumococcal vaccine should be offered to all patients with cancer.⁵ As with the administration of other inactivated vaccines, the administration of the pneumococcal vaccine should be avoided during cycles of intense chemotherapy because of the anticipated poor immunogenic response; ideally, the vaccine should be given before the patient begins treatment.⁵

The two available pneumococcal vaccines are 1) the pneumococcal 13-valent conjugated vaccine (PCV13), which recently replaced the pneumococcal 7-valent conjugated vaccine (PCV7), and 2) the pneumococcal 23-valent polysaccharide vaccine (PPSV23). Low antibody response to PPSV23 has been described in the general adult population³⁵ as well as in patients with hematologic malignancies, including multiple myeloma and lymphoma, reporting protective antibody levels in only 33%–43% of individuals.^23,36,37 In a double-blind trial that compared a single dose of PCV13 with PPSV23 in 831 pneumococcal vaccine naive adults 60–64 years of age, PCV13 achieved a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13.³⁵

In search for a better immunogenic response, studies of patients with Hodgkin disease³⁸ and HIV showed that sequential vaccination with the conjugated vaccine (PCV7) followed by PPSV23 1 year later elicited functional anti-pneumococcal responses for many of the serotypes that were significantly greater than those achieved using the polysaccharide vaccine alone.^39,40 The authors concluded that the conjugate vaccine primes the immune system to provide an antibody response to the polysaccharide pneumococcal vaccine. In 2013, the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention expanded their recommendations for the pneumococcal vaccination of unvaccinated, immunocompromised patients age 19 years or more to include the administration of PCV13 followed by the administration of PPSV23 8 weeks later (Table 2).³³ In the case of patients after stem cell transplant, the recommendation is to use repeated doses of the pneumococcus-conjugated vaccine to maintain durable responses.⁶ Repeated doses of PPSV23 administered at intervals of less than 5 years result in lower antibody levels in the general population; this phenomenon is known as hypo-responsiveness and is caused by the depletion of polysaccharide-specific B cells.⁴¹

Table 2. Centers for Disease Control and Prevention Recommendations for pneumococcal vaccination in immunocompromised patients age 19-64 years and asplenic patients³³

Patient Vaccination Status	Recommendations
Unvaccinated	A single dose of PCV13 should be given, followed by a single dose of PPSV23 at least 8 weeks later.
At least 1 dose of PPSV23 received	A single dose of PCV13 should be given if 1 or more years have passed after the last dose of PPSV23.
Additional doses of PPSV23 required	The first additional dose of PPSV23 should be given at least 8 weeks after the most recent dose of PCV13 and at least 5 years after the most recent dose of PPSV23.

Abbreviations: PCV13 (pneumococcal conjugated vaccine), PPSV23 (pneumococcal polysaccharide vaccine).

Earlier randomized studies of pneumococcal vaccination had been underpowered to evaluate the efficacy against community-acquired pneumonia secondary to the vaccine strains;³⁴ however a recent multicenter study including almost 85,000 participants 65 years or older evaluating the effectiveness of PCV13 demonstrated how the vaccine offers moderate protection against the most common forms of pneumococcal community-acquired pneumonia in healthy elderly people. Over 42,500 senior citizens were vaccinated with the PCV13 from September 2008 to the end of January 2010 and the same number received a placebo. In their analysis of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 and 90 adults in the PCV13 and the placebo groups, respectively (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5) and invasive pneumococcal disease occurred in 7 and 28 adults in the PCV13 and the placebo groups, respectively (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8).⁴² The results of this study are encouraging and maybe applied to mild to moderately immunocompromised patients.

Tetanus, diphtheria, and pertussis vaccine

Bordetella pertussis causes a highly contagious upper respiratory infection known as whooping cough. Rare but serious complications can include pneumonia, encephalopathy, and seizures have been reported,⁴³ and immunocompromised patients are vulnerable to serious, often fatal, complications.⁴⁴ Moreover, in recent years, there has been a considerable increase in the cases of pertussis, with reports from California in 2010 of over 9,000 cases and 10 infant deaths.⁴⁵ The evaluation of serological evidence of immunity in patients with cancer has demonstrated a waning of immunity for Tetanus, diphtheria and acellular pertussis (Tdap) after chemotherapy. In a report by Hammarstrom et al. in patients after autologous transplantation, less than 50% of subjects had antibodies against tetanus, diphtheria, and pertussis.⁴⁶ Therefore, given that Tdap immunity may diminish over time, and the recent increase in pertussis cases,⁴⁵ a booster Tdap vaccination should be considered for patients who have completed chemotherapy.^5,43

Hepatitis B vaccine

In patients who receive cytotoxic chemotherapy, inactivated Hepatitis B virus (HBV) may reactivate and result in varying degrees of liver damage. The rate of HBV reactivation in cancer patients receiving chemotherapy can be as high as 47%.⁴⁷ Furthermore, immunosuppressed patients are more likely to remain chronically infected with HBV; among cancer patients, the rate of chronic HBV infection ranges from 18% to 26%, and HBV infection–related mortality up to 5%.^48,49 In addition, the loss of pre-existing immunity to HBV has been described in up to 50% of patients who have undergone stem cell transplant. In patients who have received chemotherapy,⁵⁰ especially anti–B-cell antibodies such as rituximab, the loss of such immunity can result in virus re-emergence with or without signs of hepatitis.⁵¹ Therefore, HBV status should be determined, and the immunization of susceptible patients strongly considered, at the time of cancer diagnosis.⁴⁷ The HBV vaccine response rate of cancer patients receiving chemotherapy was reported in a study by Weitberg et al. to be more than 70% of individuals, which has been described as adequate.⁵²

Meningococcal vaccine

Patients with cancer should follow the ACIP recommendations for meningococcal vaccine including adolescents, individuals with persistent complement component deficiency (e.g., C5–C9, properidin, factor H, or factor D) and functional or anatomic asplenia, and for adolescents with HIV infection. Similar to other non-live vaccines, meningococcal vaccine should be offered either prior to chemotherapy or once patients' immune system has recovered.⁵³ Patients who underwent radiation to the spleen and are considered to have functional asplenia⁵⁴ (i.e. if the patient has received doses greater than 30 Gy during radiation) should also be offered meningococcal vaccine following meningococcal vaccine recommendations for splenectomized patients (please see below recommendations for splenectomized patients). In terms of immune responses to the vaccine, a study by Yu et al. in pediatric patients with acute lymphocytic leukemia evaluated antibody response to meningococcal C-conjugate vaccine after chemotherapy and showed variable responses which are related to proximity to chemotherapy and total number of B cells.⁵⁵

Human papillomavirus vaccine

Human papillomavirus (HPV) is associated with the development of genital warts, anogenital cancers (including cervical, vaginal, vulvar, and anal), and oropharyngeal cancer. The ACIP and the Centers for Disease Control and Prevention recommends that HPV vaccination should be routinely given to females and males aged 11 years or 12 years old. For those not vaccinated at the target age, catch-up vaccination is recommended up to age 26 years.⁵⁶ The presence of immunosuppression is not a contraindication to HPV vaccination, and current recommendations are to follow the general vaccination schedule by the ACIP.⁵ However, the immune response may be less robust in the immunocompromised patient.⁵⁷

Hepatitis A vaccine

Immunization against Hepatitis A virus (HAV) infection should be offered to patients with cancer traveling to countries endemic for this virus, as well as for household or close contacts with an individual with an acute HAV infection, men who have sex with men, illicit drug users, populations or communities that have high endemic rates of HAV infections (also discussed in the Travel section), or are at risk of HAV outbreaks and household or close contact with children adopted from endemic countries for HAV. Primary immunization can be achieved with one dose of HAV vaccine with a booster dose given 6 to 36 months later.^58,59

The immunological response to HAV vaccine in immunocompromised patients with cancer has not been systematically assessed. In a study including solid organ transplant recipients, Günther et al. evaluated sero-conversion following 2 doses of the HAV vaccine in kidney and liver transplant recipients and found significant sero-conversion rates in 72% and 97% of patients respectively, versus 100% in healthy controls. However, after 2 years, immunity persisted in 26%–59% of the transplant recipients vs. 100% of the healthy controls;⁶⁰ thus reassessment of immunity may be indicated later on in specific situations.

Live Attenuated Vaccines

Unlike inactivated vaccines, live attenuated vaccines may pose a risk of replication of the virus after administration, and live vaccines can actually induce infection in immunocompromised patients.⁶ Therefore, physicians should carefully evaluate and discuss these vaccines' risk-benefit profile with their patients before making a recommendation regarding their use. Live attenuated vaccines could be administered at least 4 weeks before the initiation of highly immunosuppressive therapy and at least 3 months after the completion of chemotherapy; the timing of vaccination after chemotherapy may be much later depending on the immunosuppressive agents used.⁸

Varicella and zoster vaccines

Varicella zoster virus (VZV) commonly causes chickenpox in children, but it may also be seen in adults, in whom it generally can cause morbidity and mortality, especially in immunocompromised patients. The most common presentation is referred to as shingles, and other rare complications include meningoencephalitis, cerebellitis, herpes zoster ophthalmicus, and Ramsay Hunt syndrome.³⁰

Although the risk for varicella zoster due to vaccination is low,⁶¹ varicella infection associated with the vaccine can occur in patients with cancer, and the infection ranges from mild to moderately severe.⁶² To our knowledge, death has been reported in 2 different instances, one of a child who received the vaccine while undergoing consolidation chemotherapy,⁶³ and a recent report by Bhalla et al. of disseminated, fatal infection in an adult 4 years after transplantation and who had been diagnosed with a new low-grade lymphoma.⁶⁴

Therefore, the need for varicella vaccination after chemotherapy should be evaluated with caution. Vaccine seroprotection has been evaluated in children with leukemia in remission by Leung et al. who reported seroconversion rates to Varicella vaccine (Varivax, Merck, USA) of 88% after the first dose and 98% after the second dose.⁶²

In terms of Zoster vaccine (Zostavax, Merck, USA), this vaccine is recommended as a 1-time vaccination in individuals aged 60 years or older, and although it is clear that immunosuppression increases the risk of herpes zoster, there is a paucity of studies aimed at understanding the benefits and risks of administering this vaccine in this special population.⁵⁹ Tseng et al. recently reported how older patients who receive the zoster vaccine were likely to continue to derive its benefits even if they become immunosuppressed; however, the study was not able to determine zoster vaccine safety or effectiveness in cancer patients who received zoster vaccine less than 60 days before beginning chemotherapy.^65,66 This study emphasizes the need to vaccinate immunocompetent patients older than 60 years of age, as currently no recommendations can be done about Zostavax vaccination in immunocompromised individuals.

Measles, mumps, and rubella vaccine

Morbidity and mortality rates by measles can be high in patients with cancer.^67,68 In a study in Britain over 11 years including 1043 children with acute lymphoblastic leukemia; 51 children (4.9%) died while in first remission, and 15 (29.4%) of these deaths were due to measles or its complications: 10 cases of pneumonia, and 5 cases of encephalitis.⁶⁹ Furthermore, Feldman et al. showed declining rates of antibody seropositivity of previously immunized children for measles, mumps, and rubella between 64%– 77%, after receiving treatment for acute leukemia or acute lymphoid leukemia,⁷⁰ emphasizing the need to reevaluate measles immunity after chemotherapy.

Recent outbreaks of measles have been reported in the United States and overseas.⁷¹ Although the measles-mumps-rubella (MMR) vaccine is live attenuated and should not be administered to severely immunocompromised patients, it might be considered in patients after chemotherapy that are at an increased risk for measles. With reference to vaccine response, Patel et al. reported antibody response to MMR vaccine in more than 94% of children who had completed standard chemotherapy for acute leukemia, without adverse reactions.⁷²

Special Considerations in Splenectomized Patients

Anatomic or functional asplenia is frequently encountered in patients with cancer. Patients with asplenia have an increased risk for fulminant bacteremia and septicemia caused by encapsulated bacteria, which is associated with a high mortality.⁷³ In a population-based study in Sweden that included 20,000 patients who underwent splenectomy between 1970 and 2009, the risk of hospitalization or death from sepsis among these patients who underwent splenectomy for a hematologic malignancy was higher than that among patients who underwent spleen removal due to trauma.⁷⁴

Patients should undergo vaccination at least 2 weeks prior to an elective splenectomy.⁷⁵ For patients who receive vaccines after splenectomy, the antibody response to the immunizations should be measured to determine the need for booster doses, as studies in children with Hodgkin disease showed poor antibody response to vaccines given after splenectomy.⁷⁶ Compared with those of healthy individuals, the immune systems of patients with hyposplenia can mount only a small protective antibody response to polysaccharide antigens, which may result in vaccine failure. Therefore, conjugated vaccines are preferred in these patients.

The current recommended vaccines in patients immediately before or after splenectomy are vaccines against pneumococcus, Neisseria meningitidis (meningococcus), and Haemophilus influenzae type b.

Pneumococcal vaccine

Recommendations for pneumococcus vaccine for splenectomized patients are depicted in Table 2. Adults who have undergone splenectomy should be revaccinated with one dose of the pneumococcus polysaccharide vaccine 5 years after the initial immunization.⁷⁷

Meningococcal vaccine

In splenectomy patients receiving meningococcal vaccination, the immunity provided by the conjugate vaccine (Menveo, Novartis, USA, or Menactra, Sanofi-Pasteur, France) is expected to be higher and longer lasting than that provided by the polysaccharide quadrivalent meningococcal vaccine (Menomune A/C/Y/W-135, Sanofi-Pasteur, France). Although the quadrivalent meningococcal polysaccharide vaccine is the only meningococcal vaccine approved by the US. Food and Drug Administration for asplenic patients age 56 years or more,^78,79 patients who have undergone splenectomy—even those age 56 years or more—should receive the quadrivalent conjugate meningococcal vaccine.⁸⁰ This recommendation is supported by data showing that in individuals who previously received a meningococcal conjugate vaccine, antibody responses to a subsequent dose of the same vaccine were higher than those to a subsequent dose of the polysaccharide quadrivalent vaccine.⁸¹ Two new serogroup B meningococcal vaccines (Bexsero, Novartis, USA, and Trumenba, Pfizer, USA) that have been approved recently by the US. Food and Drug Administration for patients 10 to 25 years old should also be considered in asplenic patients.

Revaccination with conjugated meningococcal vaccine every 5 years is recommended for previously vaccinated adults who remain at an increased risk for infection (e.g., adults with anatomic or functional asplenia or persistent complement component deficiencies).

Haemophilus influenza b vaccine

Asplenic patients and those planned to undergo elective splenectomy should receive one dose of Haemophilus influenza b vaccine (Hib) or any Hib-containing vaccine. The Hib conjugate vaccine has been shown to be immunogenic in both children and adults who have undergone splenectomy.^82,83 Data on revaccination against Hib are not available.

Other Considerations

Travel

Immunocompromised cancer patients who wish to travel outside the United States should be referred to a travel medicine specialist who is familiar with their care and medications. Depending on the area the patient plans to visit, the pre-travel visit should include a discussion about the vaccines the patient should receive before departing (i.e., Hepatitis A, typhoid fever, polio), and steps the patient can take to reduce the risk of contracting non–vaccine-preventable illnesses such as malaria, and food- or water-borne illnesses.⁵⁹

Hepatitis A, intramuscular/subcutaneous polio and Vi capsular polysaccharide (ViCPS) are inactive vaccines, therefore considered safe in immunocompromised patients (see Hepatitis A section). Oral polio and oral typhoid vaccines (Ty21a) are live-attenuated vaccines and should not be administered in immunocompromised patients. If time does not permit adequate vaccination (e.g., patient presents 2 weeks prior to travel), consider administering gamma globulin alone or in combination with hepatitis A vaccine.⁸⁴

Patients actively receiving chemotherapy should be discouraged from traveling to high-infection-risk areas such as regions where yellow fever is endemic, locations with active disease outbreaks, and regions with limited health care facilities.⁸⁵

Household contacts

Patients' family members should remain up-to-date with their vaccinations as per the Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices guidelines. However, some caveats regarding vaccination in households that include immunocompromised patients should be considered. In general, inactivated vaccines, the MMR vaccine, and vaccine against yellow fever are safe. Live attenuated zoster vaccine (Zostavax, Merck USA) and varicella vaccine (Varivax, Merck Inc., USA) are also safe; however, immunocompromised patients should avoid contact with persons who develop skin lesions after receipt of these vaccines until such lesions clear or crust. Other vaccines require caution on the part of the patient and household members. For example, patients with severe neutropenia and those who have received a stem cell transplant should avoid contact with household members who have recently received the nasal influenza vaccine. Also, as oral rotavirus vaccine is live attenuated and the virus may persists in feces, thus immunocompromised patients should avoid contact with the soiled diapers of infants who have received the rotavirus vaccine for 4–6 weeks. The oral polio vaccine should not be administered to household members. There is not enough data for oral typhoid or cholera vaccine to make any recommendations.

Compliance

Common barriers to vaccination include a lack of access to medical care and patients' concerns about vaccine safety. Immunization rates remain low in patients with cancer. In one survey study conducted at a university-based outpatient cancer treatment clinic, of the 204 cancer patients who completed the survey, 30% had never received an influenza vaccine, 56% had never received a pneumococcal vaccine, and only 7% remembered their oncologist asking or informing them about vaccination.⁸⁶ Other studies have reported low vaccination rates among splenectomized patients; however, these rates varied depending on the vaccine: whereas the rate of pneumococcal vaccination was 85.4%, those of Hib vaccination and meningococcal vaccination were only 39.4% and 32.3%, respectively.^87,88 As patients with cancer are in constant contact with the healthcare system and have great trust in their healthcare providers, continuous efforts to evaluate and improve vaccination compliance are highly encouraged. This should be a joint mission between oncologist and primary care provider, in consultation with infectious diseases physician and pharmacist for complicated cases.

Conclusions

Patients with oncological diagnosis and undergoing chemotherapy, have in general higher risks of infection. Many of these infections can be prevented by vaccinations (Table 3). As cancer treatments improve, eliciting better outcomes, practitioners are strongly encouraged to discuss vaccinations and other aspects of preventive medicine with their patients. New vaccines are in development including recombinant CMV vaccine, inactivated zoster vaccine that might give new possibilities to prevent these specific and common infections in immunocompromised hosts.

Table 3. Practical vaccination recommendations in patients with cancer

	Dosing Schedule	Considerations	Contraindications
Influenza	Seasonal	Administration of indicated inactivated vaccines 2 or more weeks prior to chemotherapy is preferred.	Severe allergic reaction (e.g., anaphylaxis) after previous dose of any influenza vaccine; or to a vaccine component, including egg protein
Pneumococcus	Recommended	Table 2	Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component, including to any vaccine containing diphtheria toxin
Td/Tdap	Booster	Replace a Td booster for Tdap	An immediate anaphylactic reaction. Encephalopathy occurring within 7 days following DTP vaccination
Hepatitis B	3 doses at 0,1 and 6 months	All patients should be screened for immunity, and vaccinated as needed. Consider antibody measurement after last vaccine.	History of hypersensitivity to yeast or any vaccine component
Hib	Recommended for splenectomized patients. Others, usual recommendations	If patient is unimmunized, a dose of Hib should be offered after chemotherapy	Some of the combined Hib vaccines, such Hiberix, ActHib might contain natural rubber latex, which may cause allergy in latex sensitive persons.
Meningococcus	Splenectomized patients. Others, usual recommendations	For international travelers, vaccination is recommended for those visiting the parts of sub-Saharan Africa known as the “meningitis belt” during the dry season (December–June).	Vaccination with MenACWY, MPSV4, or Hib-MenCY-TT is contraindicated among persons known to have a severe allergic reaction to any component of the vaccine, including diphtheria or tetanus toxoid
Hepatitis A	Usual recommendations (see text).	Consider antibody testing in case of future exposure after 2-3 years post-vaccination.	Contraindicated if history of previous allergy to the vaccine or a component of the vaccine
MMR	CAUTION	May be considered in specific cases at least 3-6 months after chemotherapy (i.e. children not vaccinated or epidemiological situation). Recommend checking antibody level prior.	Contraindicated while on chemotherapy or radiotherapy
Varicella/Zoster	CAUTION	May be considered in children not previously vaccinated, at least 3-6 months after chemotherapy is finished (see text). There is no data for Zoster vaccination after chemotherapy.	Contraindicated if given <4 weeks of starting chemotherapy .No data is available after chemotherapy

Abbreviations: Td/Tdap (Tetanus diphtheria/ Tetanus/diphtheria/acellular pertussis), DTP (diphtheria, tetanus, and pertussis), MMR (Measles, mumps and rubella), Hib (Heamophilus b conjugated vaccine), Hiberix (GlaxoSmithKline, England), ActHib (Sanofi-Pasteur, France).

Several questions remain unanswered including evaluation of immunogenicity on patients undergoing new target chemotherapy agents, and the need for long-term boosters. Prospective-multicenter clinical trials need to be performed to better assess the efficacy of vaccination, evaluation of immunogenicity in patients undergoing new-targeted chemotherapy, as well as the establishment of a registry to provide safety data.

Disclosure of Potential Conflicts of Interest

R.F.C. has received research funding from GlaxoSmithKline. E.J. A-H. declares no conflict of interest.

Acknowledgments

We thank Mr. Joseph Munch, Scientific publications, for his editorial revision of the article.