There are two types of pneumococcal vaccines- the polysaccharide vaccine- Pneumovax®, and a conjugate vaccine- Prevenar13®. The 23-valent polysaccharide vaccine, PPSV 23, was first introduced in 1992 for “at-risk” adults. Its use was later extended to at-risk subjects above the age of 2 and to all subjects aged 65 or above.
To understand the need for 2 separate vaccines, and their applicability to subjects on biologics or DMARDs, a bit of background information is needed.
Children below the age of 2 do not make antibodies to polysaccharide antigens very well. This is because they are reliant entirely on their T-cells to prime their “usual” B-cells (also called B-2 or thymus-dependent cells). There is however, another type of B-cells, ontologically more primitive, called B-1 cells. These B-cells are thymus independent and therefore also called TI cells. It is these latter cells that are responsible for making antibodies to polysaccharide antigens. These B-1 cells are not well developed in children below the age of 2 years. Very young children thus do not respond to polysaccharide vaccines.
An ingenious way of getting around this problem is to conjugate the polysaccharide to a protein and thus make it recognisable to T cells. This principle has already been exploited in engineering vaccines against Meningococcus and H.influenzae, both of which have polysaccharide coats and affect very young children. The commonest protein conjugate used is a substance called CRM 197, a toxoid obtained by weakening the diphtheria toxin. UK was in fact the first country to introduce the conjugate vaccine against Meningoccus C.
In 2006, a 7-valent conjugate vaccine (PCV-7) was added to the childhood vaccination programme in the UK. In 2010, this was replaced by a conjugate vaccine containing 13 strains- PCV 13. One of the unexpected consequences of the introduction of conjugate Pneumococcal vaccines among children has been a fall in the incidence of Pneumococcal infections caused by vaccine serotypes among adults, and an increase in infections by serotypes not covered by the conjugate vaccines.
Further, it is important to note that the overall efficacy of PPSV23 in preventing pneumococcal bacteraemia is probably 50 to 70%. Current evidence suggests that PPV is not effective in protecting against non-bacteraemic pneumococcal pneumonia. It does not prevent otitis media or exacerbations of chronic bronchitis. The vaccine is relatively ineffective in patients with multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma (especially during treatment) and chronic alcoholism.
Studies from Africa show that the conjugate vaccine offers protection against invasive pneumococcal infections in HIV positive patients. Head to head studies on the efficacy of PPSV 23 versus PCV13 are unfortunately lacking. To my knowledge, only one such study exists, and it did not show significant difference in efficacy.
There is some evidence that the use of methotrexate with certain biologics such as Tocilizumab reduces the immunogenicity of PPSV 23 compared with stand-alone use of the biologic, although this probably doesn’t translate into a difference in clinical protection.
The American Committee on Immunization Practices, ACIP, recommends the use of both PCV13 and PPSV23 in subjects receiving immunosuppressive therapy, including those on biologics (but excluding subjects on DMARDs, who are still recommended to receive PPSV 23 alone) In subjects on biologics or other powerful immunosuppressive drugs, the ACIP recommendation is that PCV 13 should be given first, followed ideally 6 months later, (but no earlier than 8 weeks) by PPSV 23. If PPSV 23 is given first, then one must wait for a minimum of 12 months before giving PCV 13. Further doses of PPSV 23 are recommended every 5 years, but no further doses of PCV 13 are recommended.
These biologic-specific recommendations have still not been adopted by the Joint Committee on Vaccination and Immunisation in the UK and do not appear in the BSR website. However, it is likely that these will be adopted.
Special considerations apply to subjects over the age of 65. Above this age, even if the subject is no longer on biologics (say, receiving DMARDs alone or on no treatment at all), he/she should still receive a single dose of PPSV 23 upon turning 65, or later, if a dose of PPSV 23 was given within the last 5 years, i.e. there should be a minimum period of 5 years since the last dose of PPSV 23 before re-administering this vaccine.
The UK, just as in the USA, has a policy of universal immunization of subjects over age 65 with a single dose of PPSV 23. In the UK, repeat doses of PPSV 23 are only indicated for subjects with asplenia or hyposplenia (regardless of age) and in those with CKD 4 or 5 or nephrotic syndrome (regardless of age), on the premise that the level of humoral immunity declines more rapidly in such subjects. Such subjects should receive PPSV 23 every 5 years even if they are not on immunosuppression. Revaccination is well tolerated.
However, in the USA, age related Pneumococcal vaccination guidelines changed in 2014. Based on the efficacy of PCV13 in a trial of 85,000 subjects in Netherlands aged 65 and above, the ACIP recommended this year that all subjects above 65 should receive both PCV 13 and PPSV 23. Typically, PCV 13 would be given first, followed at least 8 weeks later by PPSV 23.
Pneumococcal vaccines are not live vaccines and therefore are not contraindicated in pregnant women or those receiving biologics. However, as the vaccine takes around 2 weeks to produce immunity, it is desirable that the vaccine be given at least a couple of weeks before starting the biologic, if possible. If this is not possible, the vaccine can be given at any time after starting the biologic. The exception is Rituximab, which naturally compromises humoral immunity. It is therefore expedient to wait for 6 months post-Rituximab before administering the Pneumococcal vaccine.
Subjects who have had infection with Pneumococcus must still be immunized. Immunity will be strain-specific and will not protect the subject against other serotypes of Pneumococcus. The index infection suggests that the subject might be vulnerable to infection with other strains of Pneumococcus, and therefore it would be important to immunize.
Summary
1. Subject on DMARD, below 65 years of age- 1 dose of PPSV 23
2. Subject on DMARD, above 65- additional dose of PPSV 23 ASAP after turning 65, as long as 5 years have elapsed since last dose of PPSV 23.
3. Any subject with asplenia, hyposplenia (includes coeliacs) , CKD 4 or 5, or nephrotic syndrome, on DMARD, but not on biologic, regardless of age- PPSV23 every 5 years
4. Any subject on biologic, regardless of age or other co-morbidity- Initial PCV13, followed 6 months later by PPSV 23, and then repeat PPSV 23 every 5 years, as long as subject remains on biologic. If PPSV 23 has already been given, wait 12 months before giving PCV 13, and then repeat PPSV 23 after 5 years of initial dose of PPSV 23, and then every 5 years, as long as patient remains on biologic
5. Age over 65, biologic/DMARD discontinued- One-off dose of PPSV 23 ASAP after turning 65, provided at least five years have elapsed since last dose of PPSV 23.
To understand the need for 2 separate vaccines, and their applicability to subjects on biologics or DMARDs, a bit of background information is needed.
Children below the age of 2 do not make antibodies to polysaccharide antigens very well. This is because they are reliant entirely on their T-cells to prime their “usual” B-cells (also called B-2 or thymus-dependent cells). There is however, another type of B-cells, ontologically more primitive, called B-1 cells. These B-cells are thymus independent and therefore also called TI cells. It is these latter cells that are responsible for making antibodies to polysaccharide antigens. These B-1 cells are not well developed in children below the age of 2 years. Very young children thus do not respond to polysaccharide vaccines.
An ingenious way of getting around this problem is to conjugate the polysaccharide to a protein and thus make it recognisable to T cells. This principle has already been exploited in engineering vaccines against Meningococcus and H.influenzae, both of which have polysaccharide coats and affect very young children. The commonest protein conjugate used is a substance called CRM 197, a toxoid obtained by weakening the diphtheria toxin. UK was in fact the first country to introduce the conjugate vaccine against Meningoccus C.
In 2006, a 7-valent conjugate vaccine (PCV-7) was added to the childhood vaccination programme in the UK. In 2010, this was replaced by a conjugate vaccine containing 13 strains- PCV 13. One of the unexpected consequences of the introduction of conjugate Pneumococcal vaccines among children has been a fall in the incidence of Pneumococcal infections caused by vaccine serotypes among adults, and an increase in infections by serotypes not covered by the conjugate vaccines.
Further, it is important to note that the overall efficacy of PPSV23 in preventing pneumococcal bacteraemia is probably 50 to 70%. Current evidence suggests that PPV is not effective in protecting against non-bacteraemic pneumococcal pneumonia. It does not prevent otitis media or exacerbations of chronic bronchitis. The vaccine is relatively ineffective in patients with multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma (especially during treatment) and chronic alcoholism.
Studies from Africa show that the conjugate vaccine offers protection against invasive pneumococcal infections in HIV positive patients. Head to head studies on the efficacy of PPSV 23 versus PCV13 are unfortunately lacking. To my knowledge, only one such study exists, and it did not show significant difference in efficacy.
There is some evidence that the use of methotrexate with certain biologics such as Tocilizumab reduces the immunogenicity of PPSV 23 compared with stand-alone use of the biologic, although this probably doesn’t translate into a difference in clinical protection.
The American Committee on Immunization Practices, ACIP, recommends the use of both PCV13 and PPSV23 in subjects receiving immunosuppressive therapy, including those on biologics (but excluding subjects on DMARDs, who are still recommended to receive PPSV 23 alone) In subjects on biologics or other powerful immunosuppressive drugs, the ACIP recommendation is that PCV 13 should be given first, followed ideally 6 months later, (but no earlier than 8 weeks) by PPSV 23. If PPSV 23 is given first, then one must wait for a minimum of 12 months before giving PCV 13. Further doses of PPSV 23 are recommended every 5 years, but no further doses of PCV 13 are recommended.
These biologic-specific recommendations have still not been adopted by the Joint Committee on Vaccination and Immunisation in the UK and do not appear in the BSR website. However, it is likely that these will be adopted.
Special considerations apply to subjects over the age of 65. Above this age, even if the subject is no longer on biologics (say, receiving DMARDs alone or on no treatment at all), he/she should still receive a single dose of PPSV 23 upon turning 65, or later, if a dose of PPSV 23 was given within the last 5 years, i.e. there should be a minimum period of 5 years since the last dose of PPSV 23 before re-administering this vaccine.
The UK, just as in the USA, has a policy of universal immunization of subjects over age 65 with a single dose of PPSV 23. In the UK, repeat doses of PPSV 23 are only indicated for subjects with asplenia or hyposplenia (regardless of age) and in those with CKD 4 or 5 or nephrotic syndrome (regardless of age), on the premise that the level of humoral immunity declines more rapidly in such subjects. Such subjects should receive PPSV 23 every 5 years even if they are not on immunosuppression. Revaccination is well tolerated.
However, in the USA, age related Pneumococcal vaccination guidelines changed in 2014. Based on the efficacy of PCV13 in a trial of 85,000 subjects in Netherlands aged 65 and above, the ACIP recommended this year that all subjects above 65 should receive both PCV 13 and PPSV 23. Typically, PCV 13 would be given first, followed at least 8 weeks later by PPSV 23.
Pneumococcal vaccines are not live vaccines and therefore are not contraindicated in pregnant women or those receiving biologics. However, as the vaccine takes around 2 weeks to produce immunity, it is desirable that the vaccine be given at least a couple of weeks before starting the biologic, if possible. If this is not possible, the vaccine can be given at any time after starting the biologic. The exception is Rituximab, which naturally compromises humoral immunity. It is therefore expedient to wait for 6 months post-Rituximab before administering the Pneumococcal vaccine.
Subjects who have had infection with Pneumococcus must still be immunized. Immunity will be strain-specific and will not protect the subject against other serotypes of Pneumococcus. The index infection suggests that the subject might be vulnerable to infection with other strains of Pneumococcus, and therefore it would be important to immunize.
Summary
1. Subject on DMARD, below 65 years of age- 1 dose of PPSV 23
2. Subject on DMARD, above 65- additional dose of PPSV 23 ASAP after turning 65, as long as 5 years have elapsed since last dose of PPSV 23.
3. Any subject with asplenia, hyposplenia (includes coeliacs) , CKD 4 or 5, or nephrotic syndrome, on DMARD, but not on biologic, regardless of age- PPSV23 every 5 years
4. Any subject on biologic, regardless of age or other co-morbidity- Initial PCV13, followed 6 months later by PPSV 23, and then repeat PPSV 23 every 5 years, as long as subject remains on biologic. If PPSV 23 has already been given, wait 12 months before giving PCV 13, and then repeat PPSV 23 after 5 years of initial dose of PPSV 23, and then every 5 years, as long as patient remains on biologic
5. Age over 65, biologic/DMARD discontinued- One-off dose of PPSV 23 ASAP after turning 65, provided at least five years have elapsed since last dose of PPSV 23.
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