A comprehensive overview of pneumococcal vaccination recommendations for adults in South Africa, 2022

Introduction

Worldwide, lower respiratory tract infections (LRTIs) continue to be associated with significant morbidity and mortality. The most recent Global Burden of Disease Study evaluated the global, regional, and national morbidity, mortality and aetiology of LRTIs [mainly community-acquired pneumonia (CAP) and bronchiolitis, with the latter predominantly in children] in 195 countries, between 1990 and 2016 (1). In 2016, LRTIs caused 2,377,697 deaths in people of all ages worldwide, with Streptococcus pneumoniae (pneumococcus) being the leading cause of LRTI morbidity and mortality globally, contributing to more deaths than Haemophilus influenzae, influenza virus and respiratory syncytial virus combined, and resulting in some 55.4% (1,189,937) of all deaths. LRTIs were found to be highest in sub-Saharan Africa and South/Southeast Asia. While the study noted that progress has been made globally in reducing the burden of LRTIs, particularly in younger children, it has not been equal across all ages and locations and the burden in the elderly, especially those older than 70 years of age (1,080,958 deaths), was increasing.

Furthermore, effective vaccines are available for a number of these infections, and their appropriate use could effectively reduce the burden of LRTI and pneumococcal infections, not only in children but also in the elderly and in high-risk cases (2). National recommendations for pneumococcal (and influenza) vaccination in adults in South Africa were initially published in 1999 (3); however, pneumococcal conjugate vaccines (PCV) were not available at that time and the document only described the use of the 23-polyvalent, polysaccharide vaccine (PPV23). In 2017, the adult CAP guideline in South Africa was updated and it included recommendations for use of both PPV23 and 13-valent pneumococcal conjugate vaccine (PCV13) in adults (4). The recommendations were largely based on those of the Centers for Disease Control and Prevention (CDC) in the United States (US).

With the introduction of PCV13 for use in adults in South Africa, it soon became evident that there was uncertainty among healthcare professionals regarding the efficacy, indications, and use of the different pneumococcal vaccines. Therefore, the aim of the current literature review and associated vaccination recommendations was to clarify all these issues for healthcare professionals in all spheres of practice in country, with the ultimate goal of encouraging use of these vaccines in adults, in order to decrease the significant morbidity and mortality associated with pneumococcal infections.

It is important for the authors to indicate initially some issues to the readers of this review and associated recommendations, with the hope of making the understanding of the manuscript text and Tables 1-3 clearer.

Firstly, these recommendations do deviate in two small areas from the guideline that has been published by the CDC in the US in 2021, but not from similar recommendations from several other countries, for example, Belgium, Hong Kong, India, and parts of Italy, countries that have almost identical recommendations. The major differences from that of the CDC are that the current recommendations suggest the routine use of the PCV13 vaccine (in addition to PPV23 as described in the text and table) in adults 18 years and older with comorbid conditions. This differs from that of the CDC, who do not recommend routine PCV13 use in adults with comorbid conditions. In addition, the current recommendations indicate that PCV13 should be given routinely (in addition to PPV23 as described in the text and table) in all adults 65 years of age and older, even those without high-risk and immuno-compromising conditions. This differs from that of the CDC, who recommend that PCV13 use in the elderly, outside of high-risk and immunocompromising conditions should be based on discussion and shared decision making with the patients. Reasons for this, which are based on significant differences in the current epidemiology of, and risk factors for, pneumococcal infections in South Africa and the US, are further described in the text, especially in the sections on Epidemiology, human immunodeficiency virus (HIV) and the Elderly.

Secondly, it is important to be aware that there are few or limited clinical studies in many of the different comorbid medical conditions described in this document, on which to base the vaccine recommendations and so many of the recommendations are based on review of other guidelines, including those from the US, together with expert opinion. In this document, the recommendations are clearly outlined for ease of reference for each age-based and risk-based group of conditions in Tables 1-3, together with an indication of the strengths of each recommendation as per the tables to the following:

Strength of recommendation:

• A: strong recommendation for or against;
• B: moderate recommendation for or against;
• C: weak recommendation for or against.

Quality of evidence:

• I: evidence from at least one properly randomised, controlled trial;
• II: evidence from at least one well-designed clinical trial without randomisation, from cohort or case-controlled analytic studies (preferably from more than one centre), from multiple time-series, or from dramatic results from uncontrolled experiments;
• III: evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Thirdly, the authors are aware that both the vaccine types may not be routinely available in either the public or private sectors and if they are, they may not be reimbursed at all, or else only partly reimbursed. In those situations, where PCV13 is completely unavailable, or unaffordable for the patient, but PPV23 is, healthcare practitioners are advised still to use PPV23 in their patients on its own, in the same schedules as indicated in the tables.

The members of the Working Group and the Working Group methodology are shown in Appendix 1. We present the following article in accordance with the RIGHT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-287/rc).

Overview of pneumococcal epidemiology in South Africa

Streptococcus pneumoniae, a gram-positive bacterium carried asymptomatically in the nasopharynx, is the causative agent of a broad range of diseases from non-invasive upper respiratory tract infections (URTI) to pneumococcal pneumonia, meningitis or bacteraemia (5). The isolation of the pneumococcus from a sterile site such as cerebrospinal fluid, blood, joints, peritoneum or pleura, is termed invasive pneumococcal disease (IPD). The pneumococcus is encased in a thick polysaccharide capsule, an important virulence factor, which protects the organism from phagocytosis. There are over 90 distinct pneumococcal serotypes based on the polysaccharide capsular antigens, which are the targets for the various pneumococcal vaccines. In South Africa, the currently available polysaccharide vaccine, PPV23, was registered for use in 1992. The conjugate vaccines were first registered for use in children, starting with PCV7 in April 2009, and replaced with PCV13 in April 2011. Registration of PCV13 for use in adults occurred in 2015.

Despite widespread use of pneumococcal infant vaccination programmes, IPD remains a common cause of morbidity and mortality in both children and adults (6,7). In a study published in 2016, IPD incidence amongst HIV-infected persons was 43 times higher than among HIV-uninfected persons (8). In 2018 in South Africa, IPD incidence was highest in infants (21 cases per 100,000 population) with a second peak occurring in adults 25 years and older (6 cases per 100,000 population) (9). Apart from HIV-coinfection, almost half (45%) of the persons with IPD had an underlying risk factor/condition predisposing them to infection. This included a history of smoking, underlying chronic lung disease or chronic renal disease (8). Overall, in-hospital mortality from IPD was 32%, with 23% of those presenting with pneumococcal meningitis suffering sequelae post discharge (8).

Following introduction of the PCV into the expanded programme on immunisation in 2009, antimicrobial non-susceptibility to penicillin decreased amongst young children with IPD (10). However, there has been no change in the proportion of penicillin susceptible isolates in the adult age groups over the past 10 years.

Within 4 years of the introduction of the PCV7 vaccine in South Africa, there was an overall reduction in IPD in adults aged 25–44 years, with a 57% decrease in PCV7-serotypes due to indirect herd protection (10). Unlike the US, whose elderly population experienced a dramatic decrease in IPD following vaccine introduction, overall IPD incidence in the South African population ≥65 years has largely remained unchanged (11-13). In 2018, 36% of IPD in persons ≥5 years was caused by serotypes in PCV13 and 79% in PPV23. Serotypes 8, 3, 19A, 12F and 4 were the top 5 serotypes causing IPD in this age group (8).

Since PCV introduction, South African children <5 years have experienced a 33% decline in mortality from all-cause pneumonia, but there has been no significant decline in all-cause pneumonia mortality in South African adults (14).

More than 10 years following PCV introduction, South Africa has seen some indirect effects of infant vaccination on the adult population with regard to decreased overall IPD incidence and PCV-specific serotype disease, but there is still a substantial proportion of vaccine preventable pneumococcal disease occurring in adults, particularly in those with underlying comorbidities or risk factors for developing respiratory infections.

More recently, many countries have reported a reduction in life-threatening invasive diseases including S. pneumoniae, likely attributable to coronavirus disease 2019 (COVID-19) containment policies, as well as public information campaigns (15). Social distancing efforts and mask wearing may not be sustainable measures for disease control, and therefore, vaccination of those at risk of IPD should still be prioritised.

Pneumococcal vaccines available for use in adults in South Africa

Two kinds of pneumococcal vaccines are available and registered for use in adults in South Africa. Although they have similar side effect profiles, they are different in their formulation, immunological responses, efficacies and costs (16-22) (Table 4).

Pneumococcal vaccination recommendations in different patient groups in South Africa

Pneumococcal vaccination recommendations for patients with cardiovascular (CV) diseases (CVD)

CVD are among the leading causes of morbidity and mortality in the world, especially among the elderly population (23). Well-known risk factors for ischaemic heart disease include smoking, hypertension, diabetes and dyslipidaemia, influenza and pneumococcal infections (24-26). There is considerable evidence suggesting that influenza and pneumococcal infections themselves can induce CV events, with the increased risk being due to a number of factors (27-29), which may lead to rupture of vulnerable atherosclerotic plaques leading to acute coronary syndromes (ACS).

Potential CV protective mechanisms of pneumococcal vaccination

The efficacy of pneumococcal vaccination in preventing acute myocardial infarction (MI) is not well established, mainly due to the lack of prospective randomized clinical trials and the negative results of many studies in this field (30,31). The recommendations for pneumococcal vaccination in patients with CVD are based on the consensus of experts’ opinion and retrospective epidemiological studies.

Coronary heart disease (CHD)

In a cohort of over 21,000 patients, a fourfold higher risk of MI, stroke and fatal chronic heart failure (HF) has been described in the first 30 days after pneumonia hospitalization (32). In one meta-analysis of observational studies of patients 65 years and older, pneumococcal vaccination was associated with a significantly lower risk of ACS events (33). However, other studies have failed to show any benefit and there have been no prospective randomized controlled trials evaluating the effect of pneumococcal vaccination on the clinical course of CVD (30).

Heart failure

In patients with HF, respiratory infection is associated with decompensation, hospitalisation and increased in-hospital mortality (34). In a study of CAP, it was found that most cardiac complications occurred in the first week after admission and more than 50% in the first 24 hours (35). In a multicentre study of 1,182 patients hospitalised with CAP, 32.2% had CV events in the following 30 days, and the 30-day mortality was 4 times higher in those who developed CV events compared to those who did not (36). Studies investigating cardiac complications during CAP hospitalization have clearly shown a much higher risk of HF compared with MI (37).

There is, overall, a paucity of good evidence with regard to the clinical outcomes of pneumococcal vaccination in HF patients, and this requires further research.

Pneumococcal vaccination recommendations for patients with respiratory diseases

Chronic obstructive pulmonary disease (COPD)

A number of causes, chief amongst which, are infections, can precipitate exacerbations of COPD. Although viruses are probably the most frequent aetiological agents, bacterial infections also commonly occur, inclusive of S. pneumoniae, H. influenzae, M. catarrhalis, and other Gram-negative pathogens (38). Vaccination against the pneumococcus alone therefore is unlikely to eliminate exacerbations. The most comprehensive evaluation of the efficacy of the pneumococcal vaccine is from a 2017 Cochrane meta-analysis (39) in which no mortality benefit was demonstrated, but there was a reduction in all-cause CAP [odds ratio (OR) 0.59; 95% confidence interval (CI): 0.41 to 0.85; six studies, n=1,372; GRADE (quality of the evidence): moderate], with a number needed to treat (NNT) of 19, to prevent one episode. Most importantly, there was a significant reduction in exacerbations (OR 0.60, 95% CI: 0.39 to 0.93; 4 studies, n=446; GRADE: moderate) with a NNT of 8 (95% CI: 5 to 58). Despite this, there was no difference in hospitalization for any cause and comparison of the PCV13 and PPV23, which was assessed in only one study, found no differences between the two. In a more recent small, prospective, observational study of 121 patients, PCV13 was administered to 36.4%, 24% of whom were defined as exacerbators. PCV13 use reduced the number of hospitalisations from 32% to 18% with an adjusted OR of 2.77 for hospitalisation in those that were not vaccinated (40). In a large study of 596 elderly individuals with COPD, of whom 58 had an episode of CAP, prior use of PCV13 significantly reduced the occurrence of bacteraemia and severe IPD (41).

The Advisory Committee on Immunization Practices (ACIP) recommends PPV23 for all patients with chronic respiratory disease, including COPD (42), and the Global Initiative for Chronic Obstructive Lung (GOLD) also indicates that PPV23 reduces the incidence of CAP in younger patients with significant respiratory [forced expiratory volume in one second (FEV1) ≤40% of predicted] or CV comorbidity (43). The recommendation that PPV23 be administered to patients with COPD is based on the above Cochrane meta-analysis and some older evidence in which PPV23 reduced CAP in patients <65 years with an FEV1 <40% of predicted and on the fact that PCV13 shows similar immunogenicity (41,44).

The South African recommendations for the management of COPD mention that pneumococcal and influenza vaccines reduce exacerbations but do not make a recommendation as to who should receive the pneumococcal vaccine or which one(s) should be used (45), and the evidence as to the efficacy of the pneumococcal vaccine in patients with COPD is somewhat contradictory. However, as discussed in the introduction due to the lesser impact of infant vaccination on pneumococcal infection in the elderly, we would recommend PCV13 followed by PPV23 1 year later as in patients with other comorbidities.

Asthma

Asthma is an extremely common chronic illness with an increasing incidence in many parts of the world (46,47). Infections, particularly viral, are triggers for exacerbations (48) and bacterial co-infection, the most frequent of which is S. pneumoniae, may result in sinusitis, otitis media, infective bronchitis and pneumonia (49). There is however no good evidence that pneumococcal vaccination reduces exacerbations or improves asthma control (50).

High-risk adult asthmatics have been shown in some studies to have a 2- to greater than 6-fold increased risk of IPD and pneumococcal pneumonia (51-53) and some studies, particularly in children, indicate that vaccination may reduce corticosteroid and antibiotic use (54) but without an effect on hospitalization for pneumococcal CAP (55,56).

Currently, the Global Initiative for Asthma (GINA) does not recommend pneumococcal vaccination for asthmatics whereas the World Health Organization (WHO) and ACIP do. (46,57). Vaccination is recommended in Australia for asthmatics that have frequent hospital visits or are on multiple medications, Canada recommends vaccination for those that have required medical care in the last year and the United Kingdom only if corticosteroids have been frequently administered (58).

In South African adults with asthma, PCV13 in addition to PPV23 1 year later, should be offered to those that are poorly controlled (e.g., those with daytime asthma symptoms, or need for reliever therapy ≥2 times a week, and those with any night time wakening due to symptoms) and/or require frequent need for oral corticosteroids (e.g., ≥2 courses in the past year), due to the lesser impact of infant vaccination on pneumococcal infection in adults (59,60).

Other respiratory conditions

In some publications, pneumococcal vaccines have also been recommended for use in other respiratory conditions, including suppurative lung conditions such as bronchiectasis and cystic fibrosis, interstitial and fibrotic lung conditions, as well as in smokers (current or immediate past) (61). Other reviews have specifically included conditions such as sarcoidosis, pulmonary hypertension and cor pulmonale (62). However, there is much less evidence for benefit for these conditions. In addition, certain occupations, such as welders (63) and those exposed to diesel exhaust particles (64), appear to be at risk of IPD, and might be suitable candidates for pneumococcal vaccination.

With regard to bronchiectasis, a Cochrane review in 2009 (65), found one randomised controlled open label study of 167 adults with chronic lung disease (bronchiectasis and other diseases associated with bronchiectasis) comparing PPV23 plus influenza vaccine, with influenza vaccine alone. It highlighted a significant reduction in acute infective exacerbations in the former (OR 0.48; 95% CI: 0.26 to 0.88) with the NNT for benefit being six over 2 years. The overall conclusion was that there was limited evidence for vaccinating adults with bronchiectasis.

In patients with cystic fibrosis, a 2016 Cochrane review found no randomised or quasi-randomised trials for evidence. The conclusion was that since most countries recommend routine childhood pneumococcal vaccination, future randomised trials in this setting are unlikely to occur (66).

In idiopathic pulmonary fibrosis (IPF), studies have documented that S. pneumoniae is one of the top four pathogens causing CAP in this condition, and therefore these studies and other reviews recommended pneumococcal vaccination be considered (62,67,68). In addition, animal studies have suggested that S. pneumoniae infection may possibly be associated with progression of fibrosis through the activity of its toxin, pneumolysin (69).

We would consider that all chronic respiratory disorders, irrespective of aetiology, are comorbid conditions associated with an increased risk of pneumococcal disease and therefore warrant the administration of pneumococcal vaccine, similar to that of patients with other comorbidities.

Pneumococcal vaccination recommendations for patients with inflammatory bowel disease (IBD)

The term IBD refers, largely, to two conditions, Crohn’s disease and ulcerative colitis. Guidelines from the European Crohn’s and Colitis Organisation advise that pneumococcal vaccination be considered for all patients with newly diagnosed IBD (70), the majority of whom will ultimately require immunosuppressive drug therapies, which significantly increase the risk of bacterial infection including IPD and pneumonia (71-73).

Ideally, pneumococcal vaccination should be given before initiation of immunosuppressive therapy in order to maximise the immune response, which is impaired in those on immunosuppressive drugs even after sequential administration of PCV13 followed by PPV23, with a seroconversion rate of 59% versus 81% (74). Combinations of different immunosuppressive medications resulted in a lower response to vaccination than monotherapies (75).

In patients already on any of the numerous immunosuppressive agents available, current guidelines from multiple societies and expert reviews recommend pneumococcal vaccination for all adult and paediatric IBD patients (70,76-79).

The recommended protocol for IBD in this setting is a single dose of PCV13 followed by PPV23 at least 2 months later, possibly with a second dose of PPV23 to patients on long-term immunosuppressive therapy, after 5 years, although there is little evidence to support the latter (76).

Recently monoclonal antibodies, ustekinumab and vedolizumab have been approved for management of IBD (80-82), as well as the small molecule JAK inhibitor, tofacitinib approved for ulcerative colitis (83). These molecules are less immunosuppressive (82,84), but despite this, it is reasonable to vaccinate as per the above strategies for the immunosuppressed. The monoclonals do not appear to impact the immune response, but tofacitinib may (85).

Pneumococcal vaccination recommendations for patients with chronic liver disease

Chronic liver disease and liver transplantation (LT), and the use of immunosuppressive drugs significantly increases the risk of severe infection (86-89). IPD is more frequent and more severe with cirrhosis, and in these cases who develop meningitis, S. pneumoniae is responsible for 50% of the cases, and is also the major cause of primary peritonitis in those with ascites (88). Similarly, adults with liver disease are significantly more likely to be hospitalised with pneumococcal pneumonia than those without (89), and are significantly more likely to die during pneumococcal-related hospitalisation (90). LT recipients are at very high risk for pneumococcal diseases, with an incidence of 354/100,000 person-years compared to 11.5/100,000 in the general population (88).

Whereas large studies of pneumococcal vaccination in chronic liver disease are not available (91,92), in one small study of patients with alcohol-induced cirrhosis, antibody titres after pneumococcal vaccination were similar to those of healthy controls (91).

One recent position paper recommends that all patients with autoimmune liver disease, cirrhosis, and LT recipients should receive pneumococcal vaccination (93). Although for patients with chronic liver disease, who are not receiving immunosuppressive therapies, a single dose of PPV23 is commonly recommended (76,94), we would recommend the use of PCV13 initially, followed by PPV23 1 year later. In those receiving immunosuppressive therapies or following LT the single dose of PCV13 should be followed by PPV23 ≥8 weeks later. Re-vaccination with PPV23 after 5 years should be considered (76,88,94). If possible, vaccination should precede immunosuppressive therapy (74).

Patients already vaccinated with PPV23 should receive one dose of PCV13 at least a year after the PPV23 injection, and re-vaccination with PPV23 at 5 years should be considered (76,88,94).

Pneumococcal vaccination recommendations for patients with diabetes mellitus

Patients living with either type 1 or type 2 diabetes mellitus (T1DM, T2DM) are at increased risk of various infections including pneumococcal disease and IPD. Diabetics have a six times greater risk for hospitalisation and a three times greater risk of complications from influenza or pneumonia than non-diabetics (95).

Certain additional conditions occurring in patients with diabetes mellitus, put these patients at particularly high-risk, including age ≥65 years, and those with renal failure, CVD, nephrotic syndrome and renal transplant. Pneumococcal vaccine is indicated in all adult diabetics in a schedule similar to other risk groups (96). PCV13 vaccine is recommended for all diabetic adults followed by PPV23 1 year later unless there are compelling reasons for earlier administration of PPV23, such as in cases with associated high-risk and/or immunosuppressive conditions, as indicated above.

Pneumococcal vaccination recommendations in patients with chronic kidney disease and renal transplant

Patients with chronic renal disease are at increased risk for infections, especially IPD, and they have increased morbidity and mortality from IPD, as well as recurrent pneumococcal infections (97). Additional conditions and comorbidities (e.g., advanced age, diabetes mellitus) increase the risk further (97) and nephrotic syndrome on its own, poses a significantly increased risk due, among other factors, to loss of immunoglobulins, and use of immunosuppressive therapy (98). Renal transplant also increases risk significantly due to immunosuppressive therapy (99).

Pneumococcal vaccination does not increase the risk for acute or chronic rejection in solid organ transplants, nor lead to an increased production of donor specific antibodies in those with chronic renal disease (100,101).

Despite variable antibody response and inconclusive evidence for a durable response with pneumococcal vaccination (101,102), it is mostly recommended that patients with chronic renal disease and solid organ transplants preferably receive PCV13 first followed by PPV23 8 weeks later (101,102).

Pneumococcal vaccination recommendations for patients with autoimmune inflammatory rheumatic diseases (AIRD)

In patients with AIRD, infections, particularly LRTIs, are a major cause of hospital admission and death. Numerous studies and meta-analyses have shown that the rates of pneumococcal disease are significantly higher, frequently with a higher mortality, in patients with AIRD compared with immunocompetent controls (103). This increased risk of all-cause pneumonia, pneumococcal pneumonia, and IPD may be due to the AIRD disease itself, to immunosuppressive therapies prescribed to treat these diseases, and to associated comorbidities (Table 5). “Risk-stacking” frequently occurs in AIRD patients where the risk of infection increases with increasing numbers of risk factors (104). Thus, the majority of patients with AIRD are at risk of pneumococcal disease, and vaccination should be strongly considered (105).

All therapies used to treat AIRDs, particularly the B cell-depleting therapy, rituximab, can reduce the efficacy of vaccination (106). To ensure the optimal response to vaccines, an early vaccination strategy is recommended before immunosuppressive therapy is started. In the case of rituximab, vaccination should ideally take place at least 4 weeks before the therapy. In cases when this time window for immunization is not possible, vaccination can be offered to patients already using immunosuppressive therapy, taking into consideration a potential suboptimal response to vaccine (107). This group should receive stepwise pneumococcal vaccination, with PCV13 followed by PPV23, 8 weeks later (108). Revaccination with PPV23 after 5 years is recommended.

Pneumococcal vaccination recommendations for patients with haematology/oncology diseases

Pneumococcal vaccination in splenectomised patients

Splenectomised patients are vulnerable to overwhelming sepsis by encapsulated organisms, and in particular the pneumococcus (109). It is routine practice to administer PPV23, where possible at least 2 weeks (but preferably 4–6 weeks) before performing a splenectomy although with access to the PCV13 this vaccine has become the agent of choice (110). If that is not possible, for example, in trauma cases, the recommendation is to vaccinate patients with PPV23 2 weeks post splenectomy. In patients who have not been exposed to PCV13, this should be given first, followed 8 weeks later by PPV23 and an additional PPV23 dose can be given 5 years later (110). Patients remain at life-long risk of pneumococcal sepsis and should be educated to insist upon prompt antibiotic treatment against S. pneumoniae upon developing a febrile illness.

Pneumococcal vaccination in patients with haemoglobinopathies, such as sickle cell disease (SCD)

Due to the hyposplenism that occurs in SCD, vaccination against S. pneumoniae is necessary, because of the high risk for IPD (96). The recommendations would be the same as those described for patients with splenectomy. In addition, antibiotic prophylaxis is usually given in the young, which may be given life-long (111,112).

Pneumococcal vaccination in patients with haematological and oncological malignancies

Antibody responses after vaccination in these patients are significantly lower than those in the immunocompetent, yet may reduce the burden of pneumococcal disease (113). The vaccination is administered to stable cancer patients post-chemotherapy, usually with PCV13 followed by PPV23 at least 8 weeks later, with a repeat of the latter after 5 years (114).

Vaccination is seen as essential in cancer patients, although the evidence is based on other vulnerable populations (115). It is not known when the vaccine should be administered, or if it would be effective in patients on newer therapies, such as the immune checkpoint inhibitors, or those on chimeric antigen receptor T-cell (CAR T-cell) therapy. A 2021 position paper recommended that PCV13 should be administered even with B-cell aplasia, even though it would probably be of limited effectiveness, followed by PPV23 after B-cell recovery (116). Immunoglobulin replacement therapy, which is frequently co-administered to these patients, also impairs the immune response. The schedule for re-vaccination after CAR T-cells, should follow that recommended for haematopoietic stem cell transplant (HSCT).

Vaccination schedules in HSCT recipients

HSCT is intensely immunosuppressive, and immune-reconstitution can take months to years. Although the evidence for vaccination efficacy is low, it is nevertheless strongly recommended (76,115). Vaccination strategies against pneumococcal infection in HSCT recipients is as follows:

In phase 1, three consecutive doses of PCV13 are recommended, at least 1 month apart, initiated 3 to 6 months post HSCT (117). In patients with graft-versus-host disease, the schedule is typically delayed until immunosuppression has been weaned.

In phase 2, one dose of PPV23 is recommended 2 months after completion of phase 1. This schedule is immunogenic and well-tolerated; however, an optimal strategy to maintain long-term sero-protection remains to be established (118). This enhanced intensity vaccination schedule against pneumococcal and other infections needs to be administered, and monitored, in specialised units.

Pneumococcal vaccination recommendations for people living with human deficiency virus infection

Despite the increased uptake and access to antiretroviral therapy (ART), people living with HIV (PLHIV) are still susceptible to developing severe pneumococcal disease. This is despite CD4⁺ cell count recovery on ART, possibly due to slow and incomplete recovery of anti-pneumococcal host defenses (119). This risk is increased by avoidable aspects of lifestyle, such as smoking, excessive alcohol consumption and intravenous drug abuse, which further intensify immunosuppression (119).

The availability and use of vaccines for children and adults has not substantially changed the incidence of IPD, with morbidity and mortality remaining high in both groups (7,119). Furthermore, a study in South Africa reported that PLHIV had an incidence of IPD that was 43 times higher than in HIV-uninfected persons, with ART use at the time of the study being 40% in those eligible, which had a relatively small impact on the IPD incidence (9). The risk for both IPD and CAP remains high for PLHIV even in those who have high CD4⁺ cell counts and are virally suppressed (120). Despite longstanding international recommendations for pneumococcal vaccination, coverage remains low in many parts of the world.

Vaccination is recommended for all PLHIV regardless of their CD4⁺ cell count but is best when the HIV viral load is <1,000 copies/mL, and the choice of either PCV13, or PPV23, or both, is a balance between the available resources, according to the South African HIV vaccination guideline (121). The “prime-boost” immunisation approach is favoured; first vaccinating with PCV13 followed by PPV23 8 weeks later (121). Alternatively, PCV13 could be given alone, while for those who are to receive PPV23 as the primary vaccine, this vaccine should be administered to those who have achieved virological suppression on ART regardless of the CD4⁺ cell count (121).

Pneumococcal vaccination recommendations for patients with congenital/acquired immunodeficiency disorders, including complement deficiencies

Inborn errors of immunity (IEI), of which there are now 406 distinct disorders listed in the 2019 International Union of Immunological Societies (IUIS) classification, manifest with increased susceptibility to a broad or narrow spectrum of infections, as well as immune dysregulation phenotypes, e.g., autoimmunity, allergy or malignancy (122). Several polygenic IEI, such as common variable immunodeficiency (CVID) manifest in a similar manner to monogenic diseases. Unlike live vaccines, which are contraindicated in many IEI, inactivated vaccines such as pneumococcal vaccines are generally safe and well tolerated. However, the immunogenicity, efficacy and hence recommended use, differ depending on the different groups of IEI (Table S1). In severe abnormalities of cellular and humoral immunity, e.g., severe combined immunodeficiency or agammaglobulinaemia with absent B-cells, there would be no response to the vaccines so they are not recommended. Furthermore, these patients are frequently receiving immunoglobulin replacement therapy, which contains pneumococcal antibodies, affording some protection without vaccination (123). In contrast, in certain IEI such as terminal complement deficiencies or innate immune defects there is a particular susceptibility to encapsulated bacterial infections, including S. pneumoniae. In this setting vaccination with both PCV13 and PPV23 for expanded serotype coverage is recommended as part of treatment, with boosting after 5 years with PPV23. In the diagnostic work-up of suspected functional antibody deficiencies, assessment of polysaccharide T-independent B-cell responses using PPV23 is recommended (123), with checking of serotype-specific pneumococcal antibody responses 4 weeks after vaccination; assessment of T-dependent B-cell responses to protein conjugates is usually performed to tetanus and diphtheria rather than PCV13. In other IEI groups, such as auto-inflammatory or immune dysregulation disorders, without B-cell defects, pneumococcal vaccination is recommended in line with that for the healthy population (124).

PCV13 should be administered initially followed by PPV23 8 weeks later (125). However, if PPV23 has been given prior to PCV13 as part of the diagnostic work-up of antibody deficiency, most groups recommend addition of PCV13 ≥1 year later (126).

Pneumococcal vaccination recommendations for adults 65 years of age and older

Older adults have complex needs and vaccination tends to be a neglected aspect of their care that should be integrated into a holistic healthcare program (127).

PPV23 and PCV13 are said to have similar effectiveness in preventing IPD in older adults (PPV23 50–80% versus PCV13 75%) (128). However, comparisons on prevention of mucosal disease, such as non-bacteraemic pneumonia, are challenging, due to differences in study techniques and the lack of validated and standardized diagnostic tests (19,129,130). PCV13 has been confirmed to be effective in reducing both bacteraemic (46%) and non-bacteraemic (45%) vaccine-type pneumococcal pneumonia. While some studies have documented PPV23 to be effective in preventing pneumococcal pneumonia in elderly people, this protection wanes over time and with increasing age (128,130).

The “prime boost” technique of administering the PCV13 followed sequentially by PPV23 in order to enhance and prolong the immune response, in other words enhanced immunogenicity, while at the same time adding potential cover for the additional serotypes contained in PPV23, has been studied, but the results have not been consistent (131). However, a recent real world effectiveness study (test-negative design) of pneumococcal vaccination with PCV13 versus PPV23, versus sequential PCV13/PPV23 in adults ≥65 years noted that for the group as a whole, there was no significant difference in vaccine effectiveness between PCV13 (40.0%; 95% CI: 15.9% to 95.4%) versus PPV23 (11.0%; 95% CI: −26.4% to 37.3%) (132). Furthermore, in the younger subset of patients (aged 65–74 years), sequential PCV13/PPV23 was associated with the highest adjusted vaccine efficacy (80.3%; 95% CI: 15.9% to 95.4%), compared with that of PCV13 (66.4%; 95% CI: 0.8% to 88.6%), and then PPV23 (18.5%; 95% CI: −38.6% to 52.0%).

An additional dose of PPV23 is used in some countries between 5 and 10 years after the preceding dose; however, the effectiveness wanes with age and the safety and benefits over the age of 75 years are uncertain (42). If the first dose of PPV23 was given before the age of 65 years, then a second dose can be given after the age of 65 years provided at least 5 years have passed. Addressing other co-morbidities may be more important in those aged >75 years (127).

Two early cost-effectiveness studies of use of PCV13 and/or PPV23 in different scenarios in adults, including cases without comorbidity, aged 50, 60, or 65 years old were conducted. Both noted that one dose of PCV13 in adults was cost-effective compared to other vaccine interventions, but the analyses in both these studies were sensitive to the anticipated progressive increase in indirect protection in adults from childhood immunization (133,134). However, based on a consideration of data from the CAPITA study, additional immunogenicity data, and the study by Stoecker and colleagues (134), the ACIP recommended in 2014 that PCV13 be used in series with PPV23 in all adults ≥65 years (135). However, the ACIP also noted that there would be a reassessment of this recommendation in the future, based among other factors, on the anticipated increase in herd protection and its impact on the long-term utility of routine use of PCV13 in the elderly (135).

With regard to the indirect benefits of PCV13 vaccination, it has been demonstrated that childhood vaccination against pneumococcal disease with the conjugate vaccine has resulted, in many countries, in a substantial reduction in disease in older adults via herd protection, due to reduced nasal carriage; however, in South Africa, despite some herd protection, the impact on the age group >65 years has been limited, as mentioned in the introduction (10,136-138). In countries, such as the US, a maximal indirect benefit to older adults from vaccinating children has been reached that is not enhanced by subsequent direct vaccination with PCV13 in older adults, despite reasonable uptake (42). However, in South Africa, there is still considerable PCV13-serotype disease in both children and adults, including even younger adults, such that the IPD incidence has remained stable over 5 years up to 2019 (139).

In the light of all these data, we recommend the routine use of both PCV13 and PPV23, sequentially, for all South Africans ≥65 years. If patients are vaccine-naïve, without immunocompromise or high-risk conditions, they should routinely be given PCV13 followed by PPV23 1 year later. Therefore, this recommendation differs from that of the US, which recommends routine PPV23 in this group of patients and only consideration of the additional use of PCV13 based on additional discussions (shared-decision making) with the patients (132,140). In vaccine-naïve elderly with immunocompromising conditions, or with cerebrospinal fluid leak (CSF) leak or cochlear implant, PPV23 should be given 8 weeks after the PCV13. PCV13 should not be given as a standalone vaccine for elderly South Africans due to limited serotype coverage, and if cost or compliance with a two-dose regimen is an issue, PPV23 alone can be given to immunocompetent patients.

Other indications for pneumococcal vaccination

In patients with the following clinical situations, not necessarily included in previous sections, pneumococcal vaccination is recommended (140,141).

CSF and cochlear implants

Any condition associated with a CSF leak, particularly of long duration, increases the risk of meningitis (142).

A cohort study in 2003 estimated the incidence of pneumococcal meningitis post insertion of cochlear implants to be greater than 30 times that of age-matched controls (143).

For these indications, the recommendation for vaccination in vaccine-naïve individuals is PCV13 followed by PPV23 8 weeks later. A subsequent dose of PPV23 is recommended 5 years after the first PPV23 dose, and consideration can be given to an additional dose at age >65 years if 5 years have elapsed since the last dose.

Solid organ transplant recipients (SOT)

SOT patients experience higher incidence and mortality rates from IPD compared to the general population, with a variable rate depending on the organ transplanted (102,144,145). Risk of death from IPD is up to 3 times higher in an undifferentiated immune-suppressed population (24%) compared to the general population (9%) (146).

Vaccine response rates may be lower in SOT recipients, with limited evidence evaluating clinical outcomes with either vaccine. Both PPV23 and PCV13 vaccines produce measurable sero-responses (147), although less so than those in healthy controls, with limited evidence of benefit from “prime boosting” and less durable response rates (102). Concerns that vaccination may increase the risk of adverse allo-responses such as rejection and generation of donor specific antibodies are not supported by safety studies (102). Solid organ transplantation candidates (pre-transplant) are more likely to develop vaccine-induced immunity compared with SOT who are receiving immunosuppressive agents (post-transplant), and as such, the latter should receive vaccination in line with the transplant recommendations and/or guidelines (148,149).

Pneumococcal vaccination recommendations for travellers

Respiratory tract infections occur commonly in travellers, even to first world destinations. This is particularly the case in those ≥65 years of age and those with comorbid conditions, or with immunocompromise from whatever cause. As such, these groups should ensure that their vaccination schedules are up to date (150-155). Mass gatherings such as the annual Hajj in Saudi Arabia and the soccer world cup (which is held every 4 years) have been associated with increased respiratory infections. During the Hajj over 50% of pilgrims have reported respiratory symptoms in some studies and pneumonia has been documented as the most frequent cause of hospital admissions from communicable disease (154). A significant percentage of pilgrims are older than 60 (more than one third from certain countries), with a number of them having comorbid conditions such as diabetes, and influenza and pneumococcal vaccination have been strongly advised for both groups (154,155).

Pneumococcal vaccination, especially in older travellers with comorbid conditions, would provide protection against this infection and potentially reduce the acquisition of multidrug-resistant vaccine serotypes from countries where they are prevalent (156,157). Immunocompromised patients account for 1–2% of travellers seen in US travel clinics, and, interestingly, tend to have itineraries similar to those of their immunocompetent counterparts. This is a heterogenous group that includes those on immunosuppressants due to organ transplantation, inflammatory and autoimmune disorders, and HIV infected individuals, all of whom would benefit significantly from pneumococcal vaccination, as discussed previously (158).

Perspective of pneumococcal vaccination recommendations for healthcare practitioners in general practice or working in primary care clinics

A General Practitioner (GP) or primary care clinic consultation offers the ideal opportunity to promote and administer the pneumococcal vaccine. Most GP or primary care clinic consultations are problem-based and the focus is on the acute complaints, history taking, examination and thereafter provision of a prescription or referral for specialist consultation. The GP or primary care practitioner should always consider who amongst their patients would benefit most from pneumococcal (and other) vaccines. The administration of the annual influenza vaccination offers a very good opportunity to suggest a pneumococcal vaccination at the same time, as they are safe to administer simultaneously. Routine vaccination should not be neglected during the COVID-19 pandemic, particularly in high-risk cases.

High-risk patients are described in each of the sections above. With an aging population, who more regularly consult with their GP or primary care practitioner for follow-up and monitoring of chronic conditions and for repeat of chronic medication prescriptions, vaccination should be discussed on each visit and the opportunity taken to educate patients and their families.

Many patients are apprehensive about vaccination as they are concerned that they may actually contract the infection from the vaccine. A brief explanation of the types of vaccines and their immunological responses is required, and an explanation that the pneumococcal vaccine does not contain either live or killed microorganisms.

Remember to get consent prior to administration of any vaccine and record the vaccination in the patient’s file. A good idea is to remove the vaccine vial wrapper from the glass vial and stick this into the patient file. Patients taking warfarin or novel oral anticoagulants require careful injection to reduce bleeding at the injection site.

It also needs to be recognised that patients with multiple comorbid conditions (a condition termed “risk stacking”) is not uncommon in older and aging patients (104). These patients have an even greater risk of pneumococcal infections that may be as high as, or even higher than, those adults with high-risk and immunocompromising conditions and this is often not considered in vaccination recommendations (104). In South Africa, in addition, as indicated previously, HIV remains a major driver of ongoing pneumococcal infections, despite the comprehensive roll-out of ART (121), while a recent modelling study indicated the cost-effectiveness of PCV13 versus PPV23 in adults in South Africa, particularly in those with HV (137)

Additional potential risk factors for CAP and/or pneumococcal infection, some not mentioned above, include cigarette smoking, excessive alcohol consumption, obesity, sleep apnoea, occupations such as welding and gold mining, and people living in confined areas, such as barracks and prisons, and it may be advisable to consider pneumococcal vaccination in these groups of patients, for some of whom specific recommendations exist (159-164).

Barriers, knowledge gaps and vaccine advocacy

Vaccinations are recommended throughout life to prevent the acquisition and spread of vaccine-preventable diseases (165). Although older adults are at risk for vaccine-preventable diseases, the primary focus of medical care for adults has focused on prevention and/or treatment of chronic comorbid conditions. The primary focus of vaccination programs, therefore, has been directed at childhood immunisation and for that reason the uptake of routine vaccinations in adults has remained very low (165).

The common barriers to use of vaccinations in adults are numerous and include, among others (165):

• Lack of recognition of the importance, benefits and safety of vaccination in adults;
• Lack of healthcare provider knowledge and/or recommendations about vaccination;
• Missed opportunities for vaccination at office, clinical or hospital visits;
• Lack of publicly-funded vaccines and of reimbursement to vaccine providers and patients;
• Lack of coordinated vaccine programs, records systems, and registries for adults.

Vaccines are effective tools for the support of adults as they age, alongside healthy diet and physical exercise; these contributing to so-called “healthy ageing” (166,167). Important steps that healthcare practitioners can take to promote vaccination include (167):

• At every visit assess patients’ vaccination status;
• Recommend vaccination strongly to each patient at every opportunity. To do this use the 4Rs as a way of remembering to do this. These are Recommend, Repeat, Remind and Review;
• Have a program in your practice for vaccine administration;
• If not, refer patients to healthcare professionals who do administer vaccines;
• Document vaccine administration and submit to registries.

It is important to remember that the healthcare professional is the patients’ best health advocate (167).

However, there are some knowledge gaps noted when developing vaccine recommendations. The most important issue is that not all vaccines have had their efficacy or effectiveness studied in randomized clinical trials in each and every medical condition, since in many conditions, proof of immunogenicity in those cases is adequate for registration of vaccines. For some medical conditions, no studies exist and this could be an avenue for future research.

In its broadest sense, advocacy is the use of information, evidence and arguments to bring about change. Vaccine advocacy is best defined as: the promotion of the best scientific knowledge, moral attitudes, and public health practice with regard to vaccination (168). This is a change, which includes but is not limited to, attitude, behaviour, policies, practices and bridging the gap from problem to solution. Improving access to vaccines for vaccine preventable infections (VPI) such as pneumococcal disease has become important in South Africa. Vaccine advocacy is an important strategy to improve access for PCV13 for adolescents and adults. The use of PCV13 for adolescents and adults is not readily available in the public health system in South Africa though the vaccine is registered for use in adults.

This document presents evidence and information advocating for the use of PCV13 and PPV23 as a vaccination strategy in adolescents and adults at high risk for invasive pneumococcal infection in South Africa. This document bridges a gap that exists in the absence of a national adult vaccination programme to support the use PCV13 for adolescents and adults. This document presents evidence that supports the use of PCV13 therefore providing an opportunity to improve policy and programs to reduce the burden of this disease in adults. The only vaccine programme supported by the National Health Department for adolescents and adults is the yearly influenza vaccine. The COVID-19 and human papillomavirus (HPV) vaccine programmes are supported by the national health department but are also supported through special access programmes. This document whilst advocating for greater access for PCV13 for adults intends changing the behaviour, practice and attitude of health care workers with respect to the use of pneumococcal vaccines in adults. Evidence suggests that increased or improved access to vaccines for adolescents and adults, includes, amongst others, having national permissive recommendations in low and middle income countries such as South Africa (169). Having a national recommendation allows for or increases awareness for vaccination, which should lead to bridging the gap that is needed to effect greater use of vaccines. This in itself may not be sufficient but are important steps in advocacy, as advocacy takes a long-term view of an issue, recognising that it takes time to effect change.

Future pneumococcal vaccines

While newer conjugate vaccines, including PCV15 and PCV20, have recently been licensed and recommended for use in the US and in parts of Europe (170), these are still some way from being licensed and recommended for use in South Africa; however, as soon as they are, this document will be updated.

Conclusions

It is hoped that this document will clarify for healthcare professionals in all spheres practice, how, where, and when pneumococcal vaccines should be used in adults in South Africa, and potentially beyond that, with the ultimate goal of substantially increasing their use, in order to reduce the significant morbidity and mortality associated with pneumococcal infections.

Acknowledgments

The authors wish to thank Dr. Mark Sonderup and Wendy Spearman for consultant support. This document has been endorsed by the following Societies/Boards: Faculty of Consulting Physicians of South Africa (FCPSA), Federation of Infectious Diseases Societies of Southern Africa, South African Clinical Haematology Society (SACHas), South African Geriatrics Society (SAGS), South African HIV Clinicians Society, South African Society of Travel Medicine (SASTM), South African Stem Cell Transplant Society (SASceTS), and South African Thoracic Society (SATS).

Funding: The development of this document with its recommendation was funded by an unrestricted educational grant from Pfizer to the Federation of Infectious Diseases Societies of Southern Africa (FIDSSA), an umbrella organization encompassing most of the individual infectious diseases societies in the South Africa. The funders played no role, whatsoever, in the design, writing, reviewing, or finalizing of the manuscript.

Footnote

Reporting Checklist: The authors have completed the RIGHT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-287/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-287/coif). CF has received honoraria for participation in Advisory Boards and Speaker’s Bureaus for MSD and Pfizer. CF reports that the development of this document and its recommendations was funded by an unrestricted educational grant from Pifzer to the Federation of Infectious Diseases Societies of Southern Africa. SD has received payment for Speaker’s Bureaus for the following organizations in the last 36 months, Pfizer, MSD, ABBVIE, and SANOFI. All these speaker activities were for educational meetings or conferences. In addition, SD has participated in Advisory Board for the following organizations, MSD, ViiV, Health/GSK, Adcock Ingram and Jansen. GAR has received honoraria for Speaker’s Bureaus from Pfizer and MSD-None recently however. MM has acted on the speaker’s bureaus of MSD, Pfizer, J&J, Aspen, Mylan and Cipla, and on the Advisory Boards of Pfizer, MSD, J&J and Mylan, has also received fully paid travel expenses to international conferences and advisory boards, and had leadership or fiduciary roles in SAHIVSOC and AVCS. MYSM has received consulting fees from Johnson & Johnson, Cipla, MSD, ViiV, 360 pharmaceuticals and Mylan, and participated on data safety monitoring boards or advisory boards for EnACT, NTZ versus SOF/DCV Study, and The CARES Study, and acts on the Southern African HIV Clinicians Society. JP has received speaker’s fees from Sanofi, Novartis and Janssen, and participated on the advisory board for Sanofi. CvV has acted on the Speaker’s Bureaus of Mylan and Viatris. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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