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Abstract

Susceptibility to infections with pneumococcal bacteria (Streptococcus pneumoniae) is substantially higher among human immunodeficiency virus (HIV)-infected individuals, and accounts for a significant burden of morbidity and healthcare costs. Pneumococcal vaccination is recommended in most countries for HIV-infected adults. Current policy in Singapore and Australia recommends the use of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) as a booster dose following the use of 13-valent pneumococcal conjugate vaccine (PCV13). Despite this, adherence to this policy has been suboptimal in Singapore. This may be related to the fact that PPSV23 has not been shown to have any impact on pneumococcal carriage (the necessary prerequisite for disease development). PPSV23 has also been associated with immune hyporesponsiveness, raising concerns over the use of this vaccine globally and, in particular, in high-risk populations. The lack of data from studies comparing PCV13 and PPSV23 has also contributed to the suboptimal uptake of pneumococcal vaccines by healthcare professionals for HIV-infected individuals. This review article discusses the key issues and importance of rigorous pneumococcal vaccination programmes for HIV-infected individuals. Current recommendations for pneumococcal vaccination of HIV-infected individuals in Singapore should be adopted more readily to reduce the burden of pneumococcal disease in this high-risk group.

Keywords

Pneumococcal HIV-infection vaccine adult

Pneumococcal disease

Streptococcus pneumoniae (the pneumococcus) is a major cause of morbidity and mortality in both children and adults globally.¹ Colonisation of the nasopharynx by the pneumococcus is the major prerequisite for disease, and in most people is asymptomatic.² Dissemination of the bacterium into the surrounding mucosal tissues can cause a range of diseases that are typically classified as either non-invasive such as otitis media, sinusitis and pneumonia or invasive pneumococcal disease (IPD) when it enters a normally sterile site, including bacteraemia (sepsis), meningitis and bacteraemic pneumonia.

The major risk factors for the development of pneumococcal disease are age, ethnicity and immune status. Children under five years of age as well as older adults over the age of 65 years are most susceptible. In adults, pneumococcal bacteria are the most frequent cause of community-acquired pneumonia (CAP). This is particularly true for places like Australia and Singapore where there is an ageing population and increased rates of CAP, making this a public health priority. In Singapore, pneumonia is the third leading cause of death, accounting for 16% of total deaths in 2011.³ Even more significant are younger adults who are immunocompromised, such as those with human immunodeficiency virus (HIV) infection, who are at greater risk for susceptibility to recurrent pneumococcal infections and for which pneumococcal vaccination coverage remains low.

HIV infection substantially increases the risk of pneumococcal disease

It has long been recognised that HIV-infected adults have a substantially higher risk of acquiring pneumococcal disease (>100-fold) than age-matched HIV-uninfected adults.^4–6 Infections with encapsulated bacteria such as S. pneumoniae are one of the most common bacterial causes of respiratory disease in HIV+ adults and children.^7–9 Moreover, individuals with HIV infection are also at higher risk for recurrent pneumococcal infections, occurring in 11% of patients in a study from the USA.¹⁰ In an earlier US study, 77% of patients with recurrent pneumococcal infections were found to have a comorbidity such as HIV.¹¹ In lower income settings such as sub-Saharan Africa, it was reported that among seropositive female sex workers, the rate of recurrent pneumococcal infections was 264 per 1000 person-years.¹² Immune susceptibility during HIV infection is associated with changes in various immune system components, including T cells, dendritic cells, neutrophils and B cells.^13–15 However, the increased risk of pneumococcal infection among HIV-infected adults is thought to be mediated through B-cell dysfunction, resulting in poorer humoral immune responses to natural infection in this population¹⁶ (Figure 1). However, despite reductions in the incidence of pneumococcal disease globally through paediatric vaccination programmes, as well as in adults due to herd immunity, the increased risk among HIV-infected adults persists, even in the context of improved antiretroviral treatment.¹⁷ Data from Canada has shown that the risk of IPD was still high among HIV+ individuals despite the widespread use of highly active antiretroviral treatment (HAART) and pneumococcal immunisation with pneumococcal polysaccharide vaccine (PPSV23).¹⁸ However, other studies have demonstrated the protective role of HAART and pneumococcal vaccination in this population.^19,20 For example, in Malawi, the use of a pneumococcal conjugate vaccine (PCV7) was found to protect against IPD caused by vaccine serotypes in HIV+ adolescents and adults.²¹ It is clear that there remains a role for pneumococcal vaccination among HIV patients although more studies are needed to fully understand the benefits of these interventions.

Figure 1.

Pneumococcal vaccination among HIV-infected individuals. HIV infection induces a range of immune system defects including reduced T and B cell numbers, lower cytokine expression and impaired pneumococcal antibody levels and function. These effects can lead to increased susceptibility to infections by Streptococcus pneumoniae, resulting in a higher risk of pneumococcal colonisation and invasion into the bloodstream causing a range of conditions such as pneumonia, meningitis and sepsis. Pneumococcal vaccines can reduce the risk of pneumococcal disease in HIV-infected individuals by restoring critical immune responses primarily involving B cells and antibody function (opsonophagocytosis).

Furthermore, while first-line treatment for pneumococcal infection is usually the administration of antibiotics, this does not impact overall disease burden and results in the emergence of antibiotic resistant strains. In Singapore, like many other countries, increasing rates of antimicrobial resistance have been reported over the last 10 years.²² This is particularly important among HIV+ individuals, where increasing antibiotic resistance of pneumococci is well-documented, and is a significant challenge in the treatment of these life-threatening infections. Increased resistance of pneumococci to penicillin G was found to occur as a result of antimicrobial therapy with beta-lactams or trimethoprin-sulfamethoxazole in HIV+ patients.^23,24 Therefore, efforts to prevent pneumococcal disease among HIV-infected adults through vaccination should be a continued priority.

Pneumococcal vaccination for HIV-infected individuals

Pneumococcal vaccination of infants has had a remarkable impact on the incidence of IPD as well as limiting the circulation of serotypes in the community. For adults, vaccination rates in Singapore and elsewhere are much lower than in children, with factors such as patient education and the healthcare system contributing to this.²⁵ Among HIV+ adults, vaccination is recommended in most countries although coverage for many vaccines, including pneumococcal vaccines, remains low.²⁶ In the USA, pneumococcal vaccine coverage among adults increased marginally by 2.8% (to 23%) during 2014–2015, despite recommendations for its use, particularly in high-risk populations.²⁷ For pneumococcal vaccination, the low vaccine coverage may also be due to confusion by healthcare providers on which pneumococcal vaccine to use. Vaccination against pneumococcal infection among HIV-infected adults has been recommended for some time, although the clinical efficacy is controversial. Two currently available vaccines are licensed for use in adults in most developed countries; the pneumococcal polysaccharide vaccine (PPSV23) and the newly-licensed 13-valent pneumococcal conjugate vaccine (PCV13) (Table 1). Pneumococcal vaccines have an excellent safety profile, with only a marginal incidence of serious adverse events.²⁸ However, repeated vaccination with PPSV23 has been associated with an increased rate of adverse reactions, possibly related to the antigen dose, although this is not clearly understood. In Australia, the Therapeutic Goods Administration temporarily suspended repeat vaccination with PPSV23 on account of an increase in mild adverse reactions, and it was subsequently recommended only for immunocompromised individuals.

Table 1.

Vaccine	Serotypes	Age group recommended
PCV13	1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F	<2 years;Older adults >65 years;<65 years with co-morbidities^a
PPSV23	1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F	2–64 years with co-morbidities;≥65 years

Usual recommendation is in combination with PPSV23 for high-risk groups, for example, HIV-infection.

PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine.

Historically, HIV-infected adults have been recommended to receive a dose of PPSV23, with revaccination at least every five years. In recent times, the US Advisory Committee on Immunization Practices (ACIP) has since modified these recommendations following Food and Drug Administration approval of PCV13 in adults, and Singapore’s guidelines now reflect this change to include a first dose of PCV13 with a PPSV23 booster dose at least eight weeks later under Medisave. Table 2 summarises these recent updates to pneumococcal vaccination among adults and high-risk populations.²⁹ The reality is that in Singapore, vaccination of HIV-infected adults is suboptimal, despite best efforts to adhere to these recommendations. In 2010, Tan Tock Seng Hospital, one of the largest public hospitals in Singapore, introduced a pre-discharge vaccination programme involving pneumococcal (PPSV23) and influenza vaccines in an attempt to increase adult vaccination rates, similar to the Healthy People 2020 programme launched in the USA. Such programmes have reported encouraging results of a five-fold increase in vaccination rates in hospitalised adults since it was started.³⁰ However, it is still unclear how effective PPSV23 vaccination has been among older adults, especially for HIV-infected high-risk groups.

Table 2.

Risk group/underlying medical condition	Intervals for PPSV23–PCV13 sequence, by age group
Risk group/underlying medical condition	19–64 years	≥65 years
No underlying chronic conditions	NA	≥1 year
Immunocompetent persons Chronic heart diseaseChronic lung diseaseDiabetes mellitusAlcoholism^a Chronic liver disease, cirrhosis^a Cigarette smoking^a	NA	≥1 year
Immunocompetent persons Cerebrospinal fluid leakCochlear implant	≥1 year	≥1 year
Persons with functional or anatomic asplenia Sickle cell disease/other haemaglobinopathyCongenital or acquired asplenia	≥1 year	≥1 year
Immunocompromised persons Congenital or acquired immunodeficiencyHuman immunodeficiency virus infectionChronic renal failureNephrotic syndromeLeukaemiaLymphomaHodgkin diseaseGeneralised malignancyIatrogenic immunosuppressionSolid organ transplantMultiple myeloma^a	≥1 year	≥1 year

Recommendations for vaccination naïve patients ≥65 years. Patients who previously received PPSV23 at 65 years of age are recommended to receive PCV13 ≥1 year later. Patients who previously received PPSV23 before 65 years of age and who are now 65 years are recommended to receive PCV13 ≥1 year later, and another dose of PPSV23, that is ≥5 years since the first dose of PPSV23. Adapted from updated ACIP recommendations in Kobayashi et al.²⁹

PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine.

The key question for HIV-infected adults is, which vaccine or vaccine schedule provides optimal protection against pneumococcal disease? While the PPSV23 vaccine contains 23 of the most frequent disease-causing serotypes, it is poorly immunogenic in infants <2 years of age and so is only given to older children and adults. In contrast, PCV13 contains 13 serotypes but is highly immunogenic in children <2 years of age. Importantly, in contrast to PCV13, PPSV23 does not have any impact on vaccine-type carriage from the nasopharynx despite current recommendations for its continued use in older adults. Furthermore, the efficacy of PPSV23 remains controversial, especially in populations at higher risk of pneumococcal disease, such as HIV-infected adults. In a recent systematic review³¹ the use of PPSV23 was not found to be associated with any reduction in all-cause pneumonia or pneumococcal disease in HIV-infected adults. However, this review comprised a variety of study methodologies, including mostly observational studies (N=7) and only one randomised trial. In the randomised trial and a six-year follow-up study, conducted in Uganda in patients not receiving HAART, an almost 60% increase in all-cause pneumonia was reported in those who received PPSV23, with a 30% increase in IPD, predominantly in patients with very low CD4 T cell counts.^32,33 Results from the observational studies were mixed in terms of all pneumococcal disease, with no effect for PPSV23 found in two studies while a protective effect was found in three studies and another two for those patients with high CD4 cell counts at the time of immunisation. This is despite several studies from Africa showing similar patterns of circulating serotypes, consisting of 3, 16F, 19F and 23F,^34–36 which are all (except 16F) contained in PPSV23. In Indonesia, common circulating serotypes among HIV-infected children include 19F, 19A, 6B, 6A and 23F, while in China, the most common serotypes were 19F, 19A, 14, 6B, 23F and 15, all serotypes included in PPSV23.

An explanation for the lack of effect of PPSV23 has not been fully elucidated. Studies by our group and others have demonstrated that immunisation with PPSV23 can lead to a state of hyporesponsiveness,^37–39 resulting in an impaired immune response to revaccination with either PPSV23 or PCV13. This has been demonstrated in both healthy children and high-risk populations such as asplenic patients with β-thalassaemia⁴⁰ and thought to be due to specific depletion of pneumococcal-specific memory B cells.^41,42 However, the clinical implications of this have yet to be fully documented. In our follow-up study in Fiji, we found no long-term evidence of PPSV23-induced hyporesponse in children aged 5–7 years old.⁴³ In contrast, Indigenous Australian infants 5–23 months old who received PPSV23 were found to be at an increased risk of hospitalisation with non-viral acute lower respiratory tract infection.⁴⁴ Given the immunological dysfunction among HIV-infected individuals, PPSV23 use may not provide optimal protection and may even result in increased susceptibility to pneumococcal infection. The largest PCV13 trial to date, based in the Netherlands – the Community-acquired Pneumonia Immunisation Trial in Adults (CAPITA) study – found that it reduced both bacteraemic and non-bacteraemic pneumonia in HIV-uninfected adults by 45% and IPD by 75%.⁴⁵ However, this study compared PCV13 with a placebo, with no PPSV23 group, so it is unclear how these two vaccines compare in terms of immunogenicity and vaccine efficacy and, importantly, among HIV-infected adults. In 2011, ACIP recommended the routine use of PCV13 among adults >65 years of age, a decision based on data from the CAPITA study.

A number of studies have examined the use of pneumococcal vaccines among HIV-infected adults. A systematic review recently reported only moderate support for PPSV23 in HIV-infected adults.³¹ Most of these studies included HIV-infected adults (<50 years) with a CD4 count >200/µl and at least one year of antiretroviral treatment (ART) to ensure normal response to vaccination. In a large trial of 13,079 HIV-infected and 137,643 HIV-uninfected adults in California, PPSV23 did not have any impact on IPD in either population, with an adjusted relative risk of 13.0 (95% conﬁdence interval: 9.1–18.7).⁴ However, a recent study demonstrated similar immunogenicity following PPSV23 in newly-diagnosed HIV-infected individuals with CD4 numbers <200/µl, suggesting that delayed vaccination after 6–12 months of ART is not needed.⁴⁶ Immunogenicity and efficacy of PCV7 has been demonstrated, while for PCV13 only immunogenicity data is currently available. Vaccination with three PCV13 doses one month apart led to increased antibody and opsonophagocytic responses after dose 1 but only incremental increases after doses 2 or 3, supporting the ACIP recommendations of PCV13 use in HIV-infected individuals.⁴⁷ Comparison of PCV13–PPSV23 vaccination with PPSV23 alone found similar levels of pneumococcal serotype-specific IgG between the two groups, although there was no comparison with PCV13 alone to account for any PPSV23-induced hyporesponse when given as a booster to PCV13.⁴⁸ In Brazil, combined PCV7–PPSV23 vaccination among HIV+ adults did not enhance immunogenicity compared with PCV7 alone, suggesting that conjugate vaccination alone may have benefit.⁴⁹ In a recent study, HIV-infected adults 18–65 years immunised with a single dose of PCV13 or PPSV23 exhibited comparable pneumococcal immunity up to one year later, but as this was not a randomised controlled trial, there may have been differences in confounders and other risk factors between the two groups.⁵⁰ Immunisation of HIV-infected adults with either one or two PCV7 doses (predecessor to PCV13) resulted in long-term protective pneumococcal immunity, with two doses predictive of persistent immunity after five years, although PPSV23 was not used as a comparator vaccine in this study.⁵¹ The results of current and future studies on the efficacy of PCV13 for high-risk patients are therefore of utmost importance.

Future perspectives

Pneumococcal vaccination of high-risk populations such as those with HIV-infection should be a priority. In Singapore, pneumococcal serotypes causing disease in children are covered by current pneumococcal vaccines up to 97% of all IPD isolates,⁵² with no apparent additional benefit of using PPSV23. No data is published on serotypes causing disease among HIV+ individuals in Singapore. PCV13 is currently licensed by the US Food and Drug Administration and the Singapore Health Sciences Authority for use among adults >50 years of age. For HIV-infected adults, PCV13 followed by PPSV23 eight weeks later is the current recommendation despite the limited data for this schedule. Moreover, evidence for a clear benefit of PCV13 relative to PPSV23 has not been established. How each of these vaccines compares immunologically and their impact on pneumococcal carriage in this population over the long term are important questions that need to be addressed. While PCV13 may be more immunogenic, PPSV23 contains more serotypes and so this must be balanced against more limited but broader protection by this vaccine. In US adults, 20–25% of IPD cases and 10% of CAP were due to PCV13 serotypes, suggesting that this vaccine may still provide substantial benefits,⁵³ which are likely to be even greater among HIV-infected adults. In addition to this, programmes aimed at improving awareness of these vaccines so as to improve vaccine coverage among high-risk populations should also be investigated. One study showed that implementation of a virtual clinic improved pneumococcal vaccination coverage among HIV+ patients in the USA.²⁵ Similar strategies could be used in Singapore and elsewhere. Further studies on new-generation protein-based pneumococcal vaccines (such as the whole cell vaccine) as well as refinements to current schedules and continued surveillance will be important in the control of pneumococcal disease in these populations. Randomised controlled trials to determine vaccine efficacy and cost-effectiveness studies should provide the necessary evidence to guide appropriate pneumococcal vaccination policy and ensure optimal control of pneumococcal disease in Singapore.

Footnotes

Acknowledgements

No acknowledgements required for this manuscript.

Availability of data and materials

Not applicable.

Author contribution

PVL conceived the idea and wrote the manuscript; LP, TEL and NOT wrote the manuscript. All authors have approved this version of the manuscript.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This work was supported by the Australian National Health and Medical Research Council (NHMRC) Career Development Fellowship 2 (APP1146198) and the Victorian Government’s Operational Infrastructure Support Program.

Informed consent

Not applicable.

Ethical approval

No ethical approval was required for this manuscript.

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