New Guidance Clarifies Use of Pneumococcal, Influenza Vaccines in Older Adults

Abstract

If the federal government’s Healthy People 2020 goals are met, at least 90% of patients and residents in post-acute and long-term care facilities will be immunized against influenza and pneumococcal infection. Yet efforts to achieve near-universal vaccination rates — a goal that’s likely to extend beyond 2020 — are just one part of the public health push to lessen the burden of these infections in older adults. The other piece involves efforts to improve vaccine efficacy in older adults — particularly frail adults — by developing more immunogenic vaccines and formulating more protective immunization regimens. This push is now evidenced by an expanded menu of influenza vaccines — including a high-dose influenza vaccine that significantly reduced hospitalizations of nursing home residents in a recently published study — and by pneumococcal vaccination regimens that integrate the conjugate PCV13 vaccine for improved protection. In recently published guidance on pneumococcal vaccination aimed at clarifying confusion about the indications and timing for the vaccines, AMDA – the Society for Post-Acute and Long-Term Care Medicine offers common clinical vignettes, flow charts, and tools to help with implementation of pneumococcal vaccination programs. Outside of influenza and pneumococcal disease — the focus of regulatory efforts for immunization in nursing homes — the push to improve vaccine efficacy overall has extended to herpes zoster (shingles) as well. A new vaccine that appears to be more efficacious in older individuals is moving through the pipeline. “Our priority should always be with influenza and pneumococcal vaccination because these are life-threatening illnesses,” according to David A. Nace. MD, MPH, CMD, immediate past chair of the Society’s Infection Advisory Committee. The new shingles vaccination, however, “will probably be a game changer.” The high-dose influenza vaccine (Fluzone High-Dose; Sanofi Pasteur), a trivalent inactivated vaccine (IIV3-HD) licensed in 2009, contains four times as much antigen as standard-dose vaccines and is one of two flu vaccines licensed specifically for adults 65 and older. Influenza accounts for more than three-quarters of vaccine-preventable disease in this population. The other is an adjuvanted trivalent inactivated vaccine (aIIV3) that was licensed in 2015 (Fluad; Seqirus, Inc.). Both were approved by the Food and Drug Administration through its accelerated regulatory pathway, having demonstrated superior immunogenicity and a good safety profile, but with the requirement to show clinical benefit. The University of Pittsburgh Medical Center (UPMC) Senior Communities, where Dr. Nace serves as chief of medical affairs, moved to the high-dose vaccine for its eligible older adults for the 2015–2016 season, swayed by the results of two studies. The first, a randomized trial comparing high-dose (IIV3-HD) and standard-dose vaccines (IIV3-SD) in almost 32,000 relatively healthy older community-dwelling adults, showed a near-doubling in antibody response and a 24% reduction in laboratory-confirmed influenza among those who received the high-dose formulation (N Engl J Med 2014;371:635–645). The second was a home-grown trial for UPMC, which was the first immunogenicity study of the frail elderly in long-term care facilities. Dr. Nace and his colleagues measured antibody titers across the 2011–2012 and 2012–2013 flu seasons in about 200 residents of mean age 86.7 years who were randomized to receive either IIV3-SD or IIV3-HD. Overall, the high-dose vaccine produced titers that were about twice as high (J Infect Dis 2015;211:1915–1924). The titers generally changed little between 1 and 6 months. “More importantly, the titers for standard-dose vaccine were exceedingly low — about 10-fold lower [as the titers seen] in the community-dwelling study,” said Dr. Nace, who is also the director of long-term care and influenza programs at the University of Pittsburgh School of Medicine. The study of high-dose flu vaccine published most recently, in July 2017, zooms in on clinical benefits in nursing home residents. Investigators compared hospitalization rates among more than 38,000 residents of 823 nursing homes during the 2013–2014 flu season based on Medicare claims data. Of those, 409 administered the high-dose vaccine, and the others provided a standard dose. The hospitalization rate for respiratory illness in the 6 months after vaccination was 3.4% among high-dose residents and 3.8% among standard-dose residents, a 12.7% relative reduction. In addition, the rate of all-cause hospital admission was about 8% lower in the high-dose group than in the standard-dose group. All in all, the number needed to vaccinate to keep one resident out of the hospital during the flu season was 69 [Lancet Resp Med, July 20, 2017; https://doi.org/10.1016/S2213-2600(17)30235-7]. There was no mortality benefit from the high-dose vaccine. Still, the reductions in hospitalizations are significant because “during [each] flu season about 20% of the [nursing home] population is hospitalized, give or take a few percent,” said Stefan Gravenstein, MD, MPH, a professor at the Warren Albert Medical School and the School of Public Health at Brown University, and the study’s lead author. Moreover, the significant differences in all-cause hospitalization suggest that vaccine protection extends well beyond respiratory outcomes in older frail residents. The newer adjuvanted vaccine, Fluad, contains MF59, an oil-in-water emulsion of squalene oil that is believed to enhance the immune response. “Fluad might be just as good as the high-dose or even better. We just don’t know yet.” A secondary analysis of the study data shows, in fact, that respiratory illness as the primary reason for hospitalization accounted for only about one-third of the measured reduction in hospitalization. Other significant reasons of hospitalization were cardiovascular causes (mainly heart attacks), stroke, atrial fibrillation, and heart failure. Dr. Gravenstein reported these unpublished findings at the International Association of Gerontology and Geriatrics 2017 World Congress in July. “Flu is bigger than just pneumonia, and [the protection provided by] vaccinations extends beyond respiratory outcomes,” he told Caring. These findings build on prior research showing associations between influenza infection and an increased risk of heart attacks and stroke in older adults, as well as associations between vaccination and reductions in cardiovascular events and mortality. The reduction in hospitalization was notable for other reasons as well, Dr. Gravenstein said. For one, it occurred during a flu season in which an A/H1N1 strain was the predominant circulating virus. Because A/H1N1 strains are believed to be less virulent, the benefits seen in the study may be underestimated, he said. In addition, the mean age of the study population was 84, and one quarter were older than 90. “There’s been discussion among some smart people that vaccines are pointless if you’re too old,” and indeed, frailty has appeared to attenuate vaccine response, he said. However, “I think our study pushes back against that, given that some of the greatest effect was in the older group.” Dr. Gravenstein’s presentation was an extension of a study published in 2015, in which he and his coinvestigators first reported a significant reduction in hospitalization through an analysis of Minimum Data Set data from the study population. In this newer analysis, they accessed Medicare Part A inpatient claims as well to determine causes of hospitalization. (As disclosed by the authors, the study was funded by Sanofi Pasteur, but the company had no role in its design or analysis.) The newer adjuvanted vaccine, Fluad, contains MF59, an oil-in-water emulsion of squalene oil that is believed to enhance the immune response. Its immunogenicity has been shown to be superior to nonadjuvanted vaccines, but the data on clinical disease are not as robust as the data on Fluzone-HD, Dr. Gravenstein and Dr. Nace both said. “Fluad might be just as good as the high-dose or even better,” Dr. Gravenstein added. “We just don’t know yet.” Another relatively new influenza vaccination available for adults 65 and older is a trivalent vaccine produced through a recombinant egg-free manufacturing process. It was originally licensed for people 18 to 49, but the licensure was extended several years ago to cover all adults older than 18, based on data demonstrating adequate immunogenicity among people 50 and older. The effectiveness data specifically for the 65+ age group are not yet available, but the ability to vaccinate individuals with a severe allergy to egg holds real value, sources said. The UPMC-affiliated nursing homes, for instance, have stocked the recombinant vaccine (Flublok; Protein Sciences Corporation) for residents with a severe egg allergy and a standard-dose quadrivalent vaccine for those with a minor egg allergy, Dr. Nace told Caring, in addition to the high-dose vaccine. The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) has not given preferential status to any flu vaccine for elderly individuals in its previous seasonal influenza recommendations, and this coming flu season will be no different, said David Kim, MD, the deputy associate director for adult immunizations in the CDC’s Immunization Services Division. (ACIP’s recommendations were expected to be published by late August in the CDC’s Morbidity and Mortality Weekly Report). Quadrivalent vaccines that contain an additional B virus strain are generally replacing trivalent vaccines in the development pipeline, but Dr. Nace said the trivalent nature of the high-dose and adjuvanted flu vaccines is not of significant concern because influenza B is less likely to cause severe illness in older adults. All the influenza vaccines available for older adults in the United States are administered intramuscularly, and none contain live virus. The high-dose flu vaccine and other vaccines that are more immunogenic typically produce more local redness and soreness, but the differences between these and the less immunogenic vaccines are minor, sources said. The recombinant flu vaccine has a shorter half-life than other flu vaccines, and it expires 9 months from its production date. In 2014, ACIP called for the combined use of the long-recommended 23-valent polysaccharide vaccine, PPSV23, and the newer 13-valent conjugate vaccine, PCV13, in all adults 65 and older. ACIP was spurred to add PCV13 for adults 65 and older by a variety of findings, including data showing the impact of the vaccine’s use in children on disease in older adults (i.e., the indirect effects). Immunogenicity studies performed in frail elderly adults demonstrated strong immune responses (in both hospital and nursing home settings), and findings from a large multicenter Dutch trial demonstrated clinical efficacy. The Dutch trial — the Community-Acquired Pneumonia Immunization Trial in Adults (N Engl J Med 2015;372:1114–1125) — randomized almost 85,000 older adults (more than 26,000 were 75 years or older) to PCV13 or placebo. Those who received PCV13 had a 75% lower rate of invasive pneumococcal disease (IPD) and a 45% lower rate of pneumococcal pneumonia. Moreover, no vaccine-related serious adverse events were reported. (There was no comparison with PPSV23, as this vaccine had not been administered widely in the Netherlands.) In considering all available data, ACIP concluded that PCV13 may elicit a stronger immune response than PPSV23. However, because PPSV23 offers protection against more strains, the committee decided that the benefit of both vaccines in older adults surpassed that of either vaccine alone. (Approximately 40% of IPD in adults 65 and older is caused by serotypes unique to PPSV23, according to the CDC.) The problem was that ACIP’s 2014 recommendations sent many in long-term care into a tailspin; the Society fielded inquiries from providers, facilities, and surveyors. ACIP’s language was “confusing,” and the guidance for the intervals between shots was complex, according to members of the Society’s Infection Advisory Committee. “It was very confusing as it was,” said Swati Gaur, MD, CMD, MBA, vice chair of the Infection Advisory Committee. “And then there were payment issues — facilities [following the guidance] and not giving vaccines 1 year apart were not getting reimbursed. That affected compliance.” In 2015, ACIP issued new recommendations that simplified the intervals and clarified other points of confusion. ACIP’s intent, Dr. Gaur said, was to improve vaccine uptake and harmonize recommendations with Centers for Medicare & Medicaid Services coverage policies. Dr. Kim said there has been “a huge learning curve” and “confusion at the beginning,” but the 2015 recommendations are gaining a foothold in long-term care. Dr. Gaur and others on the Society’s Infection Advisory Committee hope that their new guidance document and its educational and implementation tools will further simplify pneumococcal vaccination (JAMDA 2017;18:99–104). The Society’s recommendations stress that unknown vaccination status should not slow the process. Providers can turn to family members, the resident’s primary care physician, or state immunization registries when information is not available in medical records, but “vaccination should not be delayed for an extended period of time in an effort to query those sources,” the guidance document says. CMS has explicitly stated that patients should not be required to present an immunization record before receiving the pneumococcal vaccine, the Society emphasizes. Nursing homes should also know, Dr. Gaur stressed, that CMS has directed its contractors not to perform vaccination audits. “They’re directed to just pay it forward,” she said. CMS has stated that patients should not be required to present an immunization record before receiving the pneumococcal vaccine. The recommended intervals for sequential use of PCV13 and PPSV23 are presented in Society recommendations in the form of flow charts and an FAQ document about common clinical situations. The Society offers common scenarios involving immunocompetent adults 65 and older and the ACIP recommended actions, such as the following: •A resident older than 65 who reports they never had the vaccine, or a resident who is unsure of their vaccine status: PCV13 should be administered first, followed by PPSV23 a year or more later. Studies have demonstrated better antibody response when PCV13 is given as the first vaccine.•A resident who previously received PPSV23 before turning 65: They should receive PCV13 upon turning 65, at least 1 year after the prior PPSV23 vaccine. A second, one-time booster dose of PPSV23 should be administered at an interval of at least 5 years after the first dose and at least 1 year after PCV13.•A resident who has had both vaccines since the age of 65: No booster doses are recommended. The interval of at least 12 months between the vaccines reflects coordination with CMS payment policies — and the desire for simplicity and better uptake — rather than medical contraindications. It is permissible to administer the two vaccines at intervals of more than 8 weeks and less than 12 months, but that might affect reimbursement. In its guidance, the Society clarifies what’s meant by “chronic renal failure” in ACIP’s recommendation to administer PCV13 in adults with chronic renal failure. The term has been replaced with chronic kidney disease (CKD), which made it unclear whether Stage 3 CKD would be covered in the ACIP recommendation, Dr. Nace said. After much research on definitions and criteria, the Infection Advisory Committee concluded, he said, that “all persons with Stages 3–5 CKD are candidates for PCV13.” The Society’s pneumococcal vaccination tools also include a Resident Pneumococcal Vaccination Assessment Note to help nursing home staff complete the required assessments of immunization status and vaccine need. Assessments should be initiated at admission and completed by day 14, and the vaccine should be administered “as soon as possible,” the recommendations say. “Administration could potentially be delayed due to issues of medical instability ... [but] it is reasonable to expect administration and documentation of pneumococcal vaccine by the first quarterly assessment or patient discharge, whichever comes first,” according to a Society statement. Reimbursement levels aside, the cost of the influenza vaccination, whether standard-dose or high-dose, is small compared with the cost of managing an influenza outbreak. Both the influenza vaccine and either of the two pneumococcal vaccines can be administered together, each in one arm, Dr. Nace said. Concerns about reimbursement have been one of the barriers to immunization, but sources said there are misperceptions. Both pneumococcal vaccines and the seasonal influenza vaccines are covered Medicare Part B benefits, and they are subject neither to the Part B deductible nor to coinsurance or copayments. Enrolled providers may roster bill for these vaccines “even if they are not a mass immunizer,” according to CMS (www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/downloads/qr_immun_bill.pdf). Many facilities “have just been writing off the cost of vaccines because it’s easier when vaccines are only $10–$15,” Dr. Gravenstein said. But with the more immunogenic vaccines costing several times more, facilities “will need to recognize they can get reimbursed the full amount and do the billing.” This does not hold true for patients on skilled status, however. And therein lies “the curve ball,” said Dheeraj Mahajan, MD, CMD, a member of the Society’s Infection Advisory Committee. Dr. Mahajan serves as the medical director of two nursing homes in the Chicago area. Vaccinations may be advisable for post-acute patients, but nursing homes “often won’t immunize until patients move into long-term care and they can charge either Medicaid or Medicare Part B,” he said. Ideally, Dr. Mahajan said, policy makers would “carve out vaccinations” from the Part A per diem. Reimbursement levels aside, Dr. Nace said, the cost of the influenza vaccination, whether standard-dose or high-dose, is small compared with the cost of managing an influenza outbreak. And as research has shown, both influenza and pneumococcal immunization can benefit even frail individuals. For tips to implement an immunization program, see "Immunization Update: Making It Happen" on page 8. Christine Kilgore is a freelance writer in Falls Church, VA.