Recommendations for influenza and Streptococcus pneumoniae vaccination in elderly people in China

Abstract Influenza and pneumonia can be prevented by vaccination, but they remain major causes of morbidity and mortality in age‐related diseases. In most areas of China, the rates of influenza and pneumococcal vaccination are relatively low and public awareness of vaccination remains insufficient. Thus, it is essential to recommend influenza and Streptococcus pneumoniae vaccination to elderly people in clinical practice. Based on recently published studies and related documents issued by several vaccination authorities, such as the World Health Organization, the National Health and Wellness Committee, the Chinese Center for Disease Control and Prevention, the US Centers for Disease Control and Prevention, and the US Advisory Committee on Immunization Practices, we propose official recommendations for influenza and S pneumoniae vaccination in elderly people in China.

the US Centers for Disease Control and Prevention, and the US Advisory Committee on Immunization Practices (ACIP). Herein, influenza and S pneumonia vaccination of elderly people in China is advocated to reduce the current burden of these preventable diseases in that population.

| Etiology and epidemiology of influenza
Influenza viruses belong to the family Orthomyxoviridae. Based on their viral nuclear proteins and matrix protein antigens, they are divided into types A, B, C, and D. Type A influenza viruses are further divided into various subtypes based on differences in the surface antigens hemagglutinin (H1-H18) and neuraminidase (N1-N11). Type B influenza and two influenza A subtypes, A/H3N2 and A/H1N1, are considered the main pathogens responsible for human influenza epidemics. [1][2][3] The epidemiological characteristics of influenza viruses include their capacity for antigenic variability and sudden outbreaks that spread rapidly, and accordingly they cause seasonal epidemics every year. Influenza outbreaks often occur in places with high population density, such as schools and nursing homes. 4 The dominant strains and activity intensity of influenza viruses in

| Disease burden of influenza in elderly people
Influenza can result in serious complications, including viral pneumonia, secondary bacterial pneumonia, encephalitis, and myocarditis, all of which can aggravate underlying medical conditions and lead to severe clinical outcomes or death. 6 Because of factors including their reduced immune responses, lung compliance, muscle strength, and coughing reflexes, as well as a disproportionate likelihood of multiple complications and malnutrition, elderly people are a high-risk population for influenza virus infection. Influenza infection in elderly people is associated with prolonged hospitalization and high influenza-related mortality. 7 Yu et al 8

| Immunogenicity and persistence
Influenza vaccination can induce humoral and cellular immune responses in humans. In humoral immunity, influenza vaccines mainly induce the production of antibodies against influenza virus surface glycoproteins. Serum antibody levels usually peak within 2-4 weeks after influenza virus infection or vaccination, but in elderly people it can take more than 4 weeks. 14,15 In the case of cellular immunity, CD8 + T lymphocytes play important roles, 16

| Application benefits
Vaccination is currently an effective way to prevent influenza in elderly people. In a meta-analysis of data derived from elderly people in China, influenza vaccine had a 53% prevention effect on influenza-like illness in recipients aged ≥60 years. 19 Liu et al 20 followed up 590 elderly people over the age of 60 years who received influenza vaccine in Beijing, and in that analysis, influenza vaccination was associated with reduced likelihood of developing "colds" (49.54%), "respiratory diseases" (64.54%), and "chronic diseases" (38.82%).
Vaccination against influenza can effectively reduce the number of influenza-related emergency medical events, hospitalizations, and deaths in elderly people. Many elderly people have chronic diseases, such as diabetes, chronic obstructive pulmonary disease, coronary heart disease, and cerebrovascular disease, and influenza vaccination may have a flow-on effect of reducing hospitalization rates and mortality rates associated with these chronic diseases in elderly people.
Vaccination is associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza and a 48% reduction in the risk of death. 21

| Safety
Inoculation with IIVs is generally safe in adults. [27][28][29][30] The most common adverse events are transient local reactions at the injection sites, such as pain, erythema, and swelling. 13 Vaccination recipients without a history of influenza vaccine antigen exposure may experience transient symptoms, such as fever, malaise, and myalgia, 31 but these do not occur frequently in adults. 32 Those who have experienced severe anaphylaxis after influenza vaccination should not seek revaccination. It has been reported that TIV recipients are more likely to develop Guillain-Barré syndrome, 33,34 but no direct relationships between influenza vaccination and the syndrome have been reported. 35 According to the monitoring data collated by the US vaccine adverse-event reporting system, the total adverse reaction rate after TIV inoculation in recipients aged ≥ 65 years was approximately 16.5 per million doses from 1990 to 2005. 36

| Current status of influenza vaccination in elderly people in China
In China, the influenza vaccination rate remains low. Yang et al 37  Center for Disease Control and Prevention, after the implementation of publicly funded vaccination, the influenza vaccination rate in elderly people was approximately 50% from 2011 to 2015, which was significantly higher than it had previously been. 39

| Worldwide guidelines on influenza vaccination in elderly people
National influenza vaccine guidelines recommend that elderly people should receive one influenza vaccination every year. 6,12,[40][41][42] The IIV or RIV are recommended by the ACIP. 12 The Canadian Immunization Advisory Committee recommends standard TIV or a high dose of TIV, a quadrivalent influenza vaccine, or a trivalent adjuvanted influenza vaccine. 6 The Australian and New Zealand Geriatrics Association, the Singapore Infection Control Association, and the Infectious Diseases Association recommend one annual vaccination, but the dosage is not clearly defined. 40

| Target population and influenza vaccination schedule
Adults aged > 60 years should receive an annual TIV before the influenza season starts. To achieve better protection, elderly people should be vaccinated annually because influenza viruses are prone to rapid antigenic mutation. When vaccine supply is limited, priority should be given to: adults with cardiovascular (excluding isolated hypertension), chronic pulmonary, hepatic, renal, hematologic, neurologic, neuromuscular, or metabolic disorders; adults who are immunocompromised; and medical staff working in health institutions, nursing homes, and sanitariums. Vaccinating health-care workers against influenza not only protects them and keeps health services running during the influenza season, it also reduces the chances of them transmitting the virus to people at high risk.

| Inoculation method
The standard vaccination procedure is one dose contained in 0.5 mL injected intramuscularly. The deltoid muscle of the upper arm is the preferred administration site. In patients with thrombocytopenia or other hemorrhagic disorders who are at a comparatively high risk of bleeding after receiving an intramuscular injection, a deep subcutaneous injection can be administered.

| Contraindications
People who are allergic to any active components, adjuvants, or trace ingredients in influenza vaccines, such as eggs (ovalbumin or chicken protein), neomycin, formaldehyde, or Triton X-100, should not be vaccinated.

| Adverse effects and management
The common adverse effects are local and systemic reactions. The local reactions include redness and swelling, pain, bruising, and induration of the injection site. 13 Systemic effects include fever, chills, headache, sweating, myalgia, joint pain, discomfort, and fatigue. 31 Those reactions generally do not require treatment and resolve spontaneously within 2 days. Rarer adverse effects include the development of a severe febrile reaction (body temperature > 39°C), which can be treated with natural cooling or medication. Some recipients may experience urticaria after vaccination. A very small minority of recipients reportedly develop anaphylactoid purpura. Such reactions should be addressed immediately via anti-allergy treatment, such as the administration of glucocorticoids. Anaphylactic shock is extremely rare, but if it occurs it must be managed actively in accordance with routine anaphylactic shock treatment principles.

| Etiology and epidemiology of pneumococcal disease
Streptococcus pneumoniae, also known as pneumococcus, is a grampositive encapsulated diplococcus bacterium. It is ubiquitous in the natural environment and humans are its primary natural host. The polysaccharide capsule of the bacterium is an essential virulence factor, and more than 90 serotypes have been defined based on differences in capsule compositions. The serotype spectrums vary in different age groups and different seasons and regions, but the general distributions of the most common pathogenic serotypes are the same throughout the world. 44 The transmission of S pneumoniae mainly occurs via direct respiratory droplets or infection caused by bacterial colonization in the respiratory tract. It spreads locally to the sinuses and middle ear, or is inhaled into the lower respiratory tract, which can lead to pneumonia. Invasive pneumococcal diseases (IPDs), such as meningitis, streptococcal pneumonia, and bacteremia, occur when the bacteria invade the bloodstream; these diseases are associated with high mortality. Streptococcus pneumoniae results in bacteremia pneumonia in approximately 20% of cases. Reportedly, up to 30 S pneumoniae serotypes are responsible for more than 80% of IPDs in all age groups globally. Although IPD cases are not as common as non-IPD infections, an etiological diagnosis is more accessible in cases of IPD. Accordingly, the incidence of IPD is often considered an important indicator of S pneumoniae serotype distribution and disease burden. 44

| Pneumococcal disease burden in elderly people
Pneumococcal infection is a major cause of morbidity and mortality in elderly people. In developed countries, the annual incidence rate of IPD is approximately 8-34/100 000, whereas in people aged ≥65 years it is approximately 24-85/100 000. 45 The mortality rates of pneumococcal bacteremia are reportedly 16%-36% in all adults 46 and 20%-40% in older patients. 47 In China, although the proportions of pneumococcal infections in cases of community-acquired pneumonia (CAP) reportedly differ in different regions, varying from 28.0% to 71.5%, 48-50 S pneumoniae is always the most common cause of CAP in elderly people. 51 The antimicrobial resistance surveillance report on S pneumoniae derived from the China Antimicrobial Resistant Surveillance System states that the respective resistance rates to penicillin, cefuroxime, and erythromycin are 53.6%, 46.4%, and as high as 94.2% in elderly people aged ≥ 65 years. 52 Pneumococcal vaccines, such as the 23-valent pneumococcal polysaccharide vaccine (PPSV) known as PPSV23, can control the prevalence of pneumococcal diseases by reducing transmission, thereby alleviating its resistance to antibiotics, which reduces the emergence of drug-resistant strains and prevents the resistance rate from rising. 53 Therefore, pneumococcal vaccination is one of most effective means of reducing S pneumoniae drug resistance.

| Development of pneumococcal vaccine
The first pneumococcal vaccine was a whole-cell preparation. The first clinical trial of a pneumococcal vaccine was conducted in 1911 in native workers at gold and diamond mines in South Africa. 54 Those vaccines were subsequently supplanted by serotype-specific PPSVs.  58 In December 2011 the FDA expanded the use of PCV13 to people aged ≥ 50 years. 59 In September 2014, the ACIP recommended the use of PCV13 in all adults aged > 65 years. 60 In China, the pneumococcal vaccine currently used in elderly people is PPSV23. 44

| Immunogenicity and persistence
Pneumococcal polysaccharide vaccine containing only polysaccharide antigen, which is a T cell-independent antigen, can induce serotype-specific immunoglobulin (Ig)A, IgM, and IgG (mainly IgG2 subclass) antibodies and promote the killing of S pneumoniae by leukocytes and phagocytic cells, thus inducing specific protective effects. Immune responses to capsular polysaccharide are agedependent and serotype-dependent. 61,62 Antibody levels initially increase after vaccination with PPSV23 and remain elevated for at least 5 years in healthy adults, but they do decline over time. 63 Antibody levels in elderly people tend to decline to approximately baseline level within 7 years after vaccination. 45 Pneumococcal conjugate vaccine can elicit interaction between T-helper lymphocytes and B lymphocytes, and induce strong immune responses and immunological memory. PCV13 can reportedly induce higher levels of antibody in elderly people than PPSV23. 60,64 Jackson et al 65 reported that in a randomized double-blind study involving 936 adults aged ≥ 70 years, the opsonophagocytic activity titers were significantly greater in a PCV13 inoculation group than in a PPSV23 group for 10 of the 12 serotypes common to both vaccines and serotype 6A, which is unique to PCV13. Opsonophagocytic activity responses after a follow-on dose of PCV13 a year later demonstrated that a prior dose of PPSV23, but not PCV13, diminished the response to a subsequent administration of PCV13, which indicates better immunogenicity of PCV13.

| Application benefits
At present, PPSV23 is effective for preventing diseases associated with 23 common S pneumoniae serotypes, and reductions in incidence, hospitalization, and mortality rates of streptococcal diseases, such as CAP and IPD, have been documented. 44 Xu et al 66 investigated 600 cases aged ≥ 60 years who were divided into a PPSV23 group and a control group. In that study, vaccination with PPSV23 was associated with reduced incidence of lower respiratory tract infection (69.7%), use of antibiotics (72.6%), and hospitalization (65.9%) during the subsequent year. Subgroup analysis indicated that PPSV23 could reduce lower respiratory tract infection, antibiotic use, and hospitalization frequency in patients with chronic obstructive pulmonary disease and coronary heart diseases, and reduce lower respiratory tract infection and antibiotic use in diabetes and hypertension patients. In a prospective study of a cohort followed from 2008 to 2011 involving 27 204 individuals aged ≥ 60 years in Spain, the risk of CAP in a recently (<5 years) PPSV23-vaccinated vaccine group was lower than that in a group that had never been vaccinated. The protective effect applied to bacteremic pneumococcal CAP, non-bacteremic pneumococcal CAP, overall pneumococcal CAP, and all-cause CAP. 67 Maruyama et al 68 reported that in a randomized double-blind trial involving 1006 adults aged ≥ 55 years, the incidence of all-cause pneumonia and pneumococcal pneumonia was significantly lower in a vaccinated group than in a placebo group, and mortality from pneumococcal pneumonia was significantly higher in the placebo group. In a meta-analysis performed by Moberley et al, 69 the PPSV23 vaccine was effective for preventing pneumonia and IPD in adults, and it was effective for preventing IPD in recipients aged ≥ 65 years. In a modeling study that added PPSV23 to the immunization schedule for elderly people in Shanghai, China, the incidence of pneumococcal disease in the PPSV23 vaccination group was lower than it was in the control group. 70 The respective cumulative incidences of CAP, IPD, and hospitalization were reduced by 3.57%, 0.02%, and 1.06%.
The combined administration of pneumococcal polysaccharide vaccination and influenza vaccination has a partially additive benefit. A meta-analysis on data derived from people aged ≥ 65 years reported in 2016 indicated that combined pneumococcal polysaccharide vaccination and influenza vaccination was associated with lower pneumonia and all-cause mortality than influenza vaccination alone. 71 Chang et al 72 analyzed 24 429 elderly people aged ≥ 75 years in Taiwan, China, and reported that compared with influenza vaccination alone, additional pneumococcal vaccination yielded additive reductions of 26% in all-cause mortality, 23%-29% in hospitalization, and 6%-13% in inpatient expenditure. Nichol 73 followed up elderly people diagnosed with chronic lung disease for three influenza seasons. In that study, influenza vaccination alone was associated with substantial reductions in hospitalization (52%) and mortality (70%), and pneumococcal vaccination alone was also associated with reductions in hospitalization (27%) and mortality (34%)-but receiving both vaccinations resulted in partially additive benefits, including a 63% reduction in hospitalization and an 81% reduction in mortality.
The results indicated that receiving both vaccines conferred additive clinical benefits in patients with chronic pulmonary diseases. In summary, previous studies have shown that simultaneous administration of influenza and pneumococcal vaccines in elderly people is effective and safe, and is not associated with increased side-effects. 74 Vaccinating older populations with PPSV23 is reportedly cost-effective. Zhao et al 70

| Safety
Some PPSV vaccine recipients may experience mild local reactions at the injection site, such as pain, swelling, and erythema, which generally resolve within 48 hours. In cases in which a subcutaneous injection is used or a second vaccination is performed, the aforementioned local reactions are relatively common. 76 Serious reactions, such as local induration at the injection site and moderate systemic symptoms, such as fever or myalgia, rarely occur, and serious systemic adverse reactions, such as anaphylaxis, are very rare. 44

| Current status of pneumococcal vaccination in elderly people in China
Data on the epidemiological surveillance of pneumococcal vaccination in elderly people in China are limited. Data from local areas indicate that pneumococcal vaccination rates are low among elderly people. In 2010, the rate of pneumococcal vaccination in residents of the Chaoyang District of Beijing aged ≥ 60 years and living in the community was 2.1%. 77 In 2014 that of male residents of the Qingpu District of Shanghai aged ≥ 65 years was 1.8%, and for female residents it was 2%. 78 In the same study, the vaccination rates were 1.6% for those aged 65-79 years, and 4.4% for those aged ≥ 80 years. In March 2015, a pneumococcal vaccination subsidy program for older residents aged ≥ 60 years was launched in Chengdu, and 1200 people were randomly selected for the survey. The vaccination rate was 42.1% in that program. 79

| Worldwide guidelines on pneumococcal vaccination in elderly people
Guidelines in most countries currently recommend one dose of PCV13 or PPSV23 in immunocompetent elderly people. [41][42][80][81][82] The Australian and New Zealand Society for Geriatric Medicine, the European Union Geriatric Medicine Society, and the International Association of Gerontology and Geriatrics-European Region all recommend PPSV23 for adults aged ≥ 65 years. Revaccination should be considered only 5-6 years after the first vaccination, and no more than two vaccinations should be administered. 41,43

| Recommendations for pneumococcal vaccination strategies in elderly people in China
The pneumococcal vaccine approved for use in elderly people in China is PPSV23. Although it has been circulated in China, PCV13 has not yet been approved for use in elderly people. Therefore, herein only recommendations pertaining to PPSV23 vaccination are provided.

| Target population and schedule of pneumococcal vaccine
Adults aged ≥ 60 years should receive one dose of PPSV23.
Revaccination is generally not recommended in immunocompetent people, but it is now recommended that elderly people who have a high risk of severe pneumococcal infection and who have been vaccinated more than 5 years previously be revaccinated. People aged ≥ 65 years who have not been vaccinated within 5 years (including those who were aged < 65 years at the time of their last vaccination) can be revaccinated. Because data on the safety of administering PPSV23 three or more times are insufficient, additional vaccinations after the first revaccination (that is, two vaccinations in total) are not routinely recommended.
Those with the following risk factors for pneumococcal infection should be given priority: chronic illness, such as chronic pulmonary disease (eg, chronic obstructive pulmonary disease, asthma, bronchiectasis); chronic cardiovascular disease (eg, congestive heart failure or cardiomyopathies, but excluding hypertension); chronic liver disease (cirrhosis); cochlear implants; diabetes mellitus; cerebrospinal fluid leaks; alcoholism; functional or anatomic asplenia (congenital or acquired asplenia, sickle cell disease or other hemoglobinopathies, splenic dysfunction, or splenectomy); and conditions associated with reduced immune function (such as congenital or acquired immunodeficiencies, HIV, nephrotic syndrome, chronic renal failure, generalized malignancy, multiple myeloma, leukemia, lymphomas, Hodgkin's disease, solid organ transplantation and bone marrow transplantation, and those receiving immunosuppressive medication, long-term systemic corticosteroids, chemotherapy, or radiation therapy). [44][45]63,83,84

| Inoculation method
The standard vaccination preparation is one dose contained in 0.5 mL, and subcutaneous or intramuscular injection is recommended. The deltoid muscle of the upper arm is the preferred administration site due to the low risk of side-effects associated with intramuscular injection at this site.

| Contraindications
People who are allergic to any component of PPSV23 should not be vaccinated.

| Adverse reactions
The most common adverse reactions are mild to moderate fever, general body temperature ≤ 38.8°C, and local reactions, such as pain, erythema, swelling, and local indurations at the injection site.
Systemic adverse reactions include weakness, fatigue, myalgia, and headache. Most of the local reactions occur within 3 days after inoculation and resolve within 5 days. The possibility of adverse reactions at the injection site after revaccination is greater than that after the first vaccination in people aged ≥ 65 years.

| Warnings and precautions
In those with severe impairment of cardiovascular and/or pulmo- Finally, all vaccine recipients should be kept under observation in the inoculation observation area for 30 minutes after immunization.

ACK N OWLE D G E M E NT S (I N PI N Y I N O R D E R O F TH E L A S T N A M E)
We would like to thank Liu Haitao (Communicable Disease Control