Vaccinations in Cancer: A Pharmacist’s Survival Guide
Rebecca Clark, PharmD
PGY-2 Oncology Pharmacy Resident
Huntsman Cancer Institute
Salt Lake City, UT
Sara deHoll, PharmD BCOP
Hematology/Oncology Clinical Pharmacist
Huntsman Cancer Institute
Salt Lake City, UT
Jordan McPherson, PharmD MS BCOP
Hematology/Oncology Clinical Pharmacist
Huntsman Cancer Institute
Salt Lake City, UT
Between January 1 and April 26, 2019, 704 cases of measles had already been reported in the United States. (This figure puts 2019 on track to have the highest number of U.S. cases reported in a single year since 1994, when 963 cases were reported.) Of the 704 cases, 71% occurred in unvaccinated persons, and 6 out of 13 reported outbreaks occurred in underimmunized settings.1 This recent outbreak not only highlights the importance of increasing vaccination efforts in the general population but warrants increased attention to ensure that individuals with cancer are being adequately screened for appropriate vaccinations.
People with cancer are at an increased risk of vaccine-preventable disease compared to the general population. Oncologic and hematologic malignancy, immunosuppressive therapy (IST), and exposure to pathogens from healthcare personnel, the environment, and nonvaccinated individuals increase the risk for infection. Although it is known that the rate of infection-related morbidity is high,2 barriers to having individuals with cancer receive vaccinations remain.3
Individuals with malignancy are at a particularly high risk for contracting influenza because of multiple risk factors, including co-infections, advanced age, comorbid conditions, and the underlying malignancy itself.4 Influenza in individuals with cancer is associated with more severe disease, a greater number of complications and hospitalizations, and higher mortality; however, adherence to recommendations for routine influenza vaccination remains low.4-6 The 2013 Infectious Diseases Society of America (IDSA) guidelines for vaccination in immunocompromised persons recommend that inactivated influenza vaccine (IIV) be given annually in cases of hematologic or solid tumor malignancy, except in those receiving anti-B-cell antibodies (e.g., rituximab) or intensive chemotherapy (defined as induction or consolidation chemotherapy in acute leukemia).7 Live attenuated influenza vaccines are not recommended. Similar recommendations are proposed by the National Comprehensive Cancer Network (NCCN) and Advisory Committee on Immunization Practices (ACIP).8,9 Guidelines recommend that IIVs be given at least 2 weeks prior to starting IST, because viral replication and development of immunologic response occur within 3 weeks of administration.10 Although the guidelines make this distinction, studies have demonstrated that immunogenicity of IIV is similar pre- and peri-IST.11,12 Considering the risk of complications from influenza in those with cancer, one can see that the benefit of annual IIV administration peri-IST in providing protection against seasonal influenza strains may outweigh potential risks.
Herpes zoster (shingles) is a disease caused by reactivation of latent varicella zoster virus (VZV) in the dorsal root and cranial nerve ganglia, most commonly caused by a decline in VZV-cellular immunity.13 Because of immune dysfunction from therapy or underlying malignancy, individuals with cancer are at a 40% higher risk of developing shingles—with the greatest risk among those with hematologic malignancies and those receiving chemotherapy. Interestingly, the risk of shingles can be elevated for up to 2 years before the initial diagnosis, likely because of diminished T-cell-mediated immunity from the underlying hematologic malignancy itself.14 The two shingles vaccines currently available are zoster vaccine live (ZVL) (Zostavax) and recombinant zoster vaccine (RZV) (Shingrix).15,16 RZV has gained widespread use since it was approved by the U.S. Food and Drug Administration in 2017. Its appeal is largely due to its better and longer-lasting efficacy and its recombinant formulation compared to ZVL.15-17 ACIP now recommends RZV for persons on low-dose IST (<20 mg/day of prednisone or equivalent).21
RZV has shown sustained efficacy of >95% in adults 50 years and older and approximately 90% efficacy in adults 70 years and older; by contrast, ZVL efficacy declines with advanced age and has only 38% efficacy in adults 70 years and older.17-20 Because of unexpected widespread use, however, RZV has been in shortage since 2018. This has led to challenges with using ZVL because current guidelines do not recommend administration of live vaccines to individuals receiving chemotherapy or radiation until they have been off therapy for at least 3 months and until evidence of substantial T-cell-mediated immunity has been seen.7,9 If ZVL is given, it should not be administered within 4 weeks of starting highly immunosuppressive therapy because administration while the patient is immunocompromised increases the risk of disseminated disease.7,15 Pharmacists should be aware of differences in efficacy, formulation, dosing schedules, route of administration, and appropriate timing of vaccinations when considering the use of either zoster vaccine product in individuals with cancer.
Underlying malignancy is also associated with a greater risk for invasive pneumococcal disease (IPD). The incidence of IPD is the highest in adults with hematologic malignancy (422.9 of 100,000 persons); the incidence in adults with solid tumor malignancies is 300.4 of 100,000 persons.22 This risk is 23- to 48-fold higher than that for healthy adults. The two pneumococcal vaccinations approved in the United States are pneumococcal polysaccharide vaccine 23-valent (Pneumovax 23/PPSV23) and pneumococcal conjugate vaccine 13-valent (Prevnar 13/PCV13)23-24. The use of pneumococcal vaccines is reported to be 65%–84% effective against IPD; however, its protective effects in immunocompromised individuals are limited, with response rates reported to be <50% in those with hematologic malignancy.22,25-27
PCV13 was initially approved in 2010 for the prevention of IPD and otitis media in infants and children and received approval the following year for prevention of pneumonia and IPD in adults 50 years and older.28 PCV13 is also recommended for adults newly diagnosed with hematologic or solid tumor malignancies.7,9 PPSV23 is recommended for adults 60 years and older and for those ages 19–59 years who are at high risk (e.g., those with malignancy or functional or anatomic asplenia). The products differ in indication, dosing schedule, presence of serotypes, and formulation.9 They also have distinct effects on the immune system. Protein-conjugated vaccines (PCVs) are associated with sustained memory cells and production of high-affinity antibodies by a T-cell-dependent response.29 In contrast, pneumococcal polysaccharide vaccines (PPSVs) do not elicit a T-cell-dependent response; therefore, production of memory B cells is reduced, decreasing the duration of protection.30 These differences in immune response are important considerations when one is determining timing, order of administration, and appropriateness of pneumococcal vaccination.
Functional and Anatomic Asplenia
The spleen is a complex secondary lymphoid organ that serves to clear blood-borne antigens, microorganisms, and aging blood cells.31 The spleen has two primary anatomic regions: the red pulp and the white pulp. The red pulp primarily contains macrophages that serve to filter blood and recycle iron. The white pulp is similar to a lymph node and contains T cells and marginal zone (MZ) B cells. In the presence of microorganisms and antigens, the white pulp regulates antigen-specific immune responses that are recruited in response to the presence of foreign antigens, produced or amplified within the spleen, and mobilized from the spleen to other tissues.32 It’s important to note that MZ B cells are uniquely capable of producing antibodies, generating memory B cells arising from the spleen, and initiating T-cell-dependent immune responses to encapsulated antigens. In addition, specific subsets of macrophages in the spleen express pathogen receptors to encapsulated bacteria, allowing for recognition and destruction of these bacteria through the complement system for adequate elimination.33 Therefore, in persons with functional or anatomic asplenia (i.e., tumor involvement in spleen, immune thrombocytopenic purpura, autoimmune hemolytic anemia, sickle cell anemia, and malignant hematologic disease), the risk of infection from encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b [Hib], and Neisseria meningitidis) is high because of decreased phagocytic activity, decreased immunoglobulin production, and depressed T-cell function. In a cohort of veterans with splenectomies, patients were at a twofold to threefold increased risk of pneumococcal pneumonia, meningitis, and septicemia, which highlights the importance of appropriate vaccinations in this population.34
No vaccine is contraindicated for this population, except for live attenuated influenza vaccines. All vaccines recommended for asplenic individuals should be administered 2 weeks before an elective splenectomy (preferred) or 2 weeks after surgery. PCV13 is recommended for asplenic patients 2 years of age and older. Subsequent doses of PPSV should follow ACIP recommendations for number of doses and timing of administration.9 One dose of Hib is recommended if it has not previously been given. Those with functional or anatomic asplenia should also be vaccinated against meningococcal groups A, B, C, Y, and W-135. Four meningococcal vaccinations are currently on the market: meningococcal (groups A/C/Y and W-135) diphtheria conjugate vaccine (Menveo and Menactra) and the meningococcal group-B vaccine (Bexsero and Trumenba). Both Menveo and Menactra contain N. meningitidis oligosaccharides conjugated to a diphtheria protein derived from C. diphtheriae to produce a robust immune response to the polysaccharide component of the vaccine.35,36 Either product is given as a two-dose series at least 8 weeks apart with revaccination every 5 years.9,35,36 Bexsero and Trumenba are composed of recombinant proteins from N. meningitidis and given as either a two-dose series (Bexsero) or a three-dose series (Trumenba). It is recommended that the same vaccine be used to complete the series because these products are not interchangeable.9,37,38
Current Challenges and Future Directions
In 2000, measles was declared eradicated from the United States. Since then, antivaccination efforts triggered by a fabricated link between autism and the measles, mumps, and rubella (MMR) vaccination have resulted in exponential year-over-year increases in measles cases.1 Cancer patients are a high-risk population for infection with measles, particularly if they have never been vaccinated with MMR. Because the MMR vaccine is a live attenuated vaccine, it is contraindicated for individuals with a severe immunodeficiency, such as those with hematologic or solid tumors or those receiving chemotherapy or IST. This presents a dilemma for cancer patients, particularly for those who have not previously received the MMR vaccine. Thus, the Centers for Disease Control and Prevention recommends that eligible family members and close contacts of those with cancer receive the two-dose MMR vaccination series in order to gain some level of protection in the patient’s environment. Caution is warranted in areas with recent outbreaks of measles cases, especially for patients undergoing treatment and those without a history of MMR vaccination.
Determining Protective Immunity for Pneumococcal and VZV Vaccines
The ability to determine protective immunity is heavily dependent on the type of assay used and the ability to correlate the results with clinical interpretation. Ideally, full protective effects from vaccinations should induce both humoral and cell-mediated immunity.39 Determining what constitutes an effective antibody response to particular vaccinations remains controversial. For example, response to the pneumococcal vaccines (PCV13 and PPSV23) is determined by the percentage of serotypes that show a twofold to fourfold increase in antibody response from baseline. Measuring antipneumococcal antibodies (PnAb) at baseline and after vaccination is the current practice for determining protective immunity. The accepted PnAb level that constitutes protective immunity for the polysaccharide vaccine is 1–1.5 µg/mL 1-month postvaccination and theoretically provides protection for 5 years. People can be classified as having deficient production of antibodies if they respond to less than 50%–70% of the serotypes analyzed in the assay.40
Because of differences in analytical methods used to define thresholds (particularly in people with cancer or immunocompromised individuals), as well as changes in the PnAb based on age, clinicians should use clinical judgment when considering patients for revaccination and should consider obtaining a PnAb level if deficient production of antibodies is suspected. Protection against VZV is highly dependent on T-cell-mediated immunity (CMI) to maintain VZV latency and minimize the severity of infection if it occurs. Unfortunately, VZV-CMI and age are negatively correlated, and no standard marker of CMI confers protection. However, the new shingles vaccine (RZV) is uniquely formulated to include a VZV glycoprotein E (gE) conjugate that is a target for the VZV-specific antibody and CD4-positive T cells.
In addition, the AS01B adjuvant system that contains gE has the ability to stimulate both humoral immunity (including VZV-specific memory immunity) and cell-mediated immunity.41 Although a measure of immune response that confers protection against herpes zoster is unknown, the immunologic response of RZV has been evaluated and is based on anti-gE antibody levels. RZV given at 0 and 2 months or 0 and 6 months showed similar immunologic response based on anti-gE levels 1 month after the second dose was given.16 For those with cancer and those who are immunocompromised, RZV is predicted to provide reactogenicity similar to that for those who are immunocompetent. Phase 1/2 trials to date in autologous transplant recipients and in people with Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or acute leukemia showed sustained immunogenicity for up to 12–18 months.41-43
To summarize, what constitutes an effective response to a particular vaccination for those with cancer remains controversial. Although newer vaccination formulations (e.g., RZV) have demonstrated immunogenicity in this population, similar research is needed for other vaccinations in order to define protective immunity.
Intravenous Immune Globulin
Intravenous immune globulin (IVIG) is a polyclonal immunoglobulin derived from pooled plasma from blood donors. It is hypothesized that polyclonal antibodies in the IVIG product can interfere with immunity against active immunizations, particularly the MMR vaccine and varicella vaccine. Passively acquired immunity from IVIG can inhibit an immune response to the MMR vaccine for 3 months or longer; however, the duration is based on the dose of IVIG given. MMR and varicella vaccines should be given at least 2 weeks before IVIG because vaccine viral replication and immune response can take 2–3 weeks to develop. If IVIG is given within 2 weeks of MMR or varicella vaccine, clinicians should consider doing serologic testing for protective immunity following completion of IVIG or readministering the vaccines per ACIP recommendations. If either vaccine cannot be given prior to IVIG, vaccination should be delayed until 3–11 months after IVIG to provide ample time for elimination of the passively acquired immune effects from IVIG.44-47 Per ACIP recommendations, typhoid, yellow fever, live influenza vaccine, zoster, and rotavirus can be given any time before, during, or after administration of IVIG.45
Immunotherapy has revolutionized the treatment of cancer. Immune checkpoint inhibitor (ICI) augmentation of T-cell immunity and blockade of programmed cell death-1 (PD-1) signaling increases virus-specific immunity.48 It is unknown whether vaccination during treatment with ICIs alters the frequency of immune-related adverse events (irAEs). Clinical trials for ICIs have varied in their guidance regarding administration of vaccinations. Data on the safety and efficacy of vaccination in patients receiving ICIs are lacking. One cohort study of 23 patients with solid tumors treated with PD-1/programmed death-ligand 1 blockade who received the seasonal influenza vaccine showed seroprotective levels similar to those of healthy age-matched controls and a higher rate of seroconversion, indicating a more robust immune response. However, the rate of irAEs was higher (52.2%) than anticipated, with 26.1% of patients experiencing a severe complication, which indicates a possible hyper-response due to cross-presentation of shared antigens.49 This finding raises the question of optimal timing of vaccination administration and safety in combination with immunotherapy. Although it is hypothesized that seroprotection against influenza is robust, larger prospective studies are needed to determine the safety and efficacy of vaccination with immunotherapy. Until more is known, caution should be taken with vaccination for patients who are receiving immunotherapy.
Identifying vaccination needs in patients with cancer has become increasingly complex in light of new vaccination formulations and a continuously changing therapeutic landscape. Hematology/oncology pharmacists should have a working knowledge of how anticancer therapies may augment the immune response to vaccination and guide optimal decision making on their use in those with cancer.
- Patel M, Lee AD, Redd SB, et al. Increase in Measles Cases—United States, January 1–April 26, 2019. MMWR Morb Mortal Wkly Rep. 2019;68(17):402-404. Available at http://dx.doi.org/10.15585/mmwr.mm6817e1.
- Ariza-Heredia EJ, Chemaly RF. Practical review of immunizations in adult patients with cancer. Hum Vaccin Immunother. 2015;11(11):2606-2614.
- Ward EM, Flowers CR, Gansler T, Omer SB, Bednarczyk RA. The importance of immunization in cancer prevention, treatment, and survivorship. CA Cancer J Clin. 2017;67(5):398-410.
- Cooksley CD, Avritscher EB, Bekele BN, Rolston KV, Geraci JM, Elting LS. Epidemiology and outcomes of serious influenza-related infections in the cancer population. Cancer. 2005;104(3):618-628.
- Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis. 2009;9(8):493-504.
- Chemaly RF, Vigil KJ, Saad M, et al. A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes. Cancer. 2012;118(18):4627-4633.
- Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):309-318.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections Version 1.2019 (October 25, 2018). Available at https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf
- Ezeanolue E, Harriman K, Hunter P, et al. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf
- Kano H, Mizuta K, Sakakihara Y, et al. Efficacy and safety of immunization for pre- and post-liver transplant children. Transplantation. 2002;74(4):543-550.
- Keam B, Kim MK, Choi Y, et al. Optimal timing of influenza vaccination during 3-week cytotoxic chemotherapy cycles. Cancer. 2017;123(5):841-848.
- Dulek DE, Halasa NB. Timing isn’t everything: influenza vaccination in cancer patients. Cancer. 2017;123(5):731-733.
- Gross G, Schöfer H, Wassilew S, et al. Herpes zoster guideline of the German Dermatology Society (DDG). J Clin Virol. 2003;26(3):277-289.
- Qian J, Heywood AE, Karki S, et al. Risk of herpes zoster prior to and following cancer diagnosis and treatment: a population-based prospective cohort study. J Infect Dis. 2018. [epub ahead of print].
- Zostavax (zoster vaccine live) [package insert]. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2006.
- Shingrix (zoster vaccine recombinant, adjuvanted) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
- Hurley LP, Allison MA, Dooling KL et al. Primary care physicians’ experience with zoster vaccine live (ZVL) and awareness and attitudes regarding the new recombinant zoster vaccine (RZV). Vaccine. 2018;36(48):7408-7414.
- Lal H, Cunningham AL, Heineman TC. Adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;373(16):1576-1577.
- Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016;375(11):1019-1032.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes and postherpatic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.
- Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. Morb Mortal Wkly Rep. 2018;67(3):103-108.
- Kyaw MH, Rose CE, Fry AM, et al. The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. J Infect Dis. 2005;192(3):377-386.
- Pneumovax 23 (pneumococcal vaccine polyvalent) [prescribing information]. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; May 2015.
- Prevnar 13 (pneumococcal conjugate vaccine [13-valent]) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals; August 2017.
- Robertson JD, Nagesh K, Jowitt SN, et al. Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer. 2000;82(7):1261-1265.
- Hinge M, Ingels HA, Slotved HC, et al. Serologic response to a 23-valent pneumococcal vaccine administered prior to autologous stem cell transplantation in patients with multiple myeloma. APMIS. 2012;120(11):935-940.
- Sinisalo M, Vilpo J, Itala M, et al. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukemia. Vaccine. 2007;26(1):82-87.
- Centers for Disease Control and Prevention. Licensure of a 13-Valent Pneumococcal Conjugate Vaccine (PCV13) and Recommendations for Use Among Children – Advisory Committee on Immunizations (ACIP). Morb Mortal Wkly Rep. 2010;59:258-261.
- Clutterbuck EA, Lazarus R, Bowman J, et al. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis. 2012;205(9):1408-1416.
- Vila-Corcoles A, Ochoa-Gondar O. Preventing pneumococcal disease in the elderly: recent advances in vaccines and implications for clinical practice. Drugs & Aging. 2013;30(5):263-276.
- Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol. 2014;166(2):165-76.
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- Kristinsson SY, Gridley G, Hoover RN, et al. Long-term risks after splenectomy among 8,149 cancer free-American veterans: a cohort study with up to 27 years follow-up. Haematologica. 2014;99(2):392-398.
- Menactra (meningococcal [groups A, C, Y and W-135] polysaccharide diphtheria toxoid conjugate vaccine) [prescribing information]. Swiftwater, PA: Sanofi Pasteur; April 2018.
- Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; October 2018.
- Bexsero (multicomponent meningococcal B vaccine) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2018.
- Trumenba (meningococcal group B vaccine) [prescribing information]. Philadelphia, PA; Wyeth; January 2018.
- Charlton CL, Lai FY, Dover DC. How to determine protective immunity in the post-vaccine era. Hum Vaccin Immunother. 2016;12(4):903-906.
- Daly TM, Hill HR. Use and clinical interpretation of pneumococcal antibody measurements in the evaluation of humoral immune function. Clin Vaccine Immunol. 2015;22(2):148-152.
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- Stadtmauer EA, Sullivan KM, Marty FM, et al. A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous hematopoietic cell transplant recipients. Blood. 2014;124(19):2921-2929.
- Berkowitz EM, Moyle G, Stellbrink HJ, et al.; Zoster-015 HZ/su Study Group. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study. J Infect Dis. 2015;211(8):1279-1287.
- Carpenter PA, Englund JA. How I vaccinated blood and marrow transplant recipients. Blood. 2016;127(23):2824-2832.
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- Laubli H, Balmelli C, Kaufmann L, et al. Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk of immune-related adverse events. J Immunother Cancer. 2018;6(1):4.