Pharmacist
"Capvaxive, which contains 8 serotypes different from other pneumococcal vaccines, may provide a new defence strategy against serotypes involved in adult invasive pneumococcal disease."
Title:
| Introduction
| What is pneumococci?
| Invasive - noninvasive pneumococcal disease - what does it mean?
| What are the statistics on pneumococcal diseases?
| Risk factors
| How many types of pneumococcal vaccines are there?
| History of pneumococcal vaccines
| What is the association between pneumococcal vaccines and antibiotic resistance?
| Pneumococcal polysaccharide vaccine (PPSV)
|
| What are the general rules for the administration of pneumococcal vaccines?
| What are the general guidelines for pneumococcal vaccination in children?
| What is Capvaxive (PCV21)?
| Who should receive Capvaxive?
| How does PCV21 differ from other PCVs, especially PCV20?
| Are there any disadvantages to using PCV21 compared to other PCVs?
| What is the safety profile of the Capvaxive vaccine?
| Last message
Introduction
On June 17, 2024, the FDA approved Capvaxive, a 21-valent conjugate vaccine for the prevention of invasive pneumococcal disease and pneumococcal pneumonia in adults 18 years of age and older. Walter Orenstein, Professor at Emory University and a member of Merck's Scientific Advisory Committee, said: "Complications from invasive pneumococcal disease can lead to hospitalization, organ damage and even death. Capvaxive is designed to contain the serotypes that cause most invasive pneumococcal disease in adults and helps protect adults against invasive pneumococcal disease and pneumococcal pneumonia."
What is pneumococci?
Streptococcus pneumoniae (pneumococcus) are gram-positive, alpha-hemolytic, facultatively anaerobic, encapsulated gram-positive bacteria with more than ninety serotypes. The polysaccharide capsule is the major virulence factor and serotypes are defined on the basis of differences in capsule structure. Pneumococcus was first isolated from the saliva of a rabies patient by Louis Pasteur in 1881. The relationship between pneumococcus and lobar pneumonia was first described in 1883, but pneumococcal pneumonia was confused with other types of pneumonia until the development of the Gram stain in 1884. Between 1915 and 1945, the chemical structure and antigenicity of the pneumococcal capsular polysaccharide, its relationship to virulence, and the role of bacterial polysaccharides in human disease were described. By 1940, more than 80 serotypes of pneumococcus had been identified. By 2020, 100 serotypes have been documented. Not all serotypes cause severe disease and may differ in their colonization frequency, ability to invade the host, antibiotic resistance profiles, and epidemiology.
Invasive - noninvasive pneumococcal disease - what does it mean?
Pneumococci can remain asymptomatically colonized in the nasopharynx or cross the mucosal barrier and cause regional respiratory infection or invasive disease by migrating to nearby tissues or the bloodstream, affecting various organ systems.
A more widespread and moderate spread to tissues close to the nasopharynx can lead to clinical manifestations such as otitis media and sinusitis.
One of the important non-invasive pneumococcal diseases is community-acquired pneumonia (when pneumococcal disease is limited to the lungs), while invasive pneumococcal diseases include pneumococcal bacteremia (infection of the bloodstream), pneumococcal meningitis (infection of the membranes of the brain and spinal cord).
S. pneumoniae is the most common cause of meningitis in adults. Its incidence in children has decreased dramatically with the use of pneumococcal vaccines.
When the term pneumonia is used, what is generally emphasized is the presence of an infection that causes consolidation (hardening and disharmony) and inflammation in the lungs. However, pneumonia is not always caused by an infectious agent, sometimes it can be caused by aspiration of any physical, chemical or allergic irritant.
Clinically, pneumonia can be classified as community-acquired, hospital-acquired, and opportunistic pneumonia. In addition, mild and severe pneumonia, which indicate the importance of the clinical condition, typical and atypical pneumonia, which are determined by the pathogen, pneumonia developing in immunocompromised patients, aspiration pneumonia and ventilator pneumonia, which is considered within hospital-acquired pneumonia, can also be counted among the types of pneumonia.
Community-acquired pneumonia is the most common clinical presentation of pneumococcal disease in adults. Patients with an onset of pneumonia outside the hospital or within 48 hours of hospitalization are considered to have community-acquired pneumonia.
Hospital-acquired pneumonia refers to pneumonia cases that are not known to be in the incubation period during hospitalization and develop within 48 hours of hospitalization or within 48 hours of hospital discharge. Ventilator-associated pneumonia is a subset of hospital-acquired pneumonia that develops within 48 hours of intubation in a patient on invasive mechanical ventilation without a history of pneumonia.
What are the statistics on pneumococcal diseases?
The World Health Organization reports that nearly 300,000 of the nearly 6 million deaths of children under the age of five worldwide are caused by pneumococcal disease.
It is estimated that more than 31,000 cases of invasive pneumococcal disease (bacteremia and meningitis) and more than 3,500 deaths occurred in the United States in 2017. Remarkably, more than half of these cases occurred in adults for whom the pneumococcal polysaccharide vaccine is indicated.
In Europe and the United States, S. pneumoniae is estimated to cause approximately 30-50% of community-acquired pneumonia in adults requiring hospitalization. In the United States, it is estimated that there are more than 150,000 hospitalizations for pneumococcal pneumonia each year and has been shown to complicate influenza infection.
Following the introduction of pneumococcal conjugate vaccine 7 (PCV7) in 2000, a dramatic reduction in invasive pneumococcal disease in children under 5 years of age has been reported. Prior to the introduction of PCV7, the rate of invasive pneumococcal disease caused by the serotypes in PCV7 among children in this age group was approximately 80 cases per 100,000 population, whereas after the introduction of PCV7, the rate of disease caused by these 7 serotypes fell dramatically to less than 1 case per 100,000 population by 2007.
The use of PCV7 in children younger than 5 years has also reduced the burden of invasive pneumococcal disease in older children and adults by reducing transmission of vaccine serotype pneumococci (community herd protection). In 1998-99, there were 40 cases per 100,000 population in adults aged 65 years and older, but after the introduction of PCV7, disease rates due to these 7 serotypes declined by 45% by 2007.
In 2007-08 (before PCV13), rates of PCV13-type invasive pneumococcal disease among children younger than 5 years were about 14 cases per 100,000. In 2014-15 (post-PCV13), rates of PCV13-type disease decreased by 87%. After the introduction of PCV13 in children, there have also been reductions in cases in older adults through herd protection.
Risk factors
Non-immunocompromised risk factors
- Children < 2 years and adults >65 years
- Chronic cerebrospinal fluid (CSF) leakage
- Decreased mucociliary function
- Cochlear implants
- Chronic heart disease
- Diabetes mellitus
- Chronic kidney disease*
- Chronic liver disease, including cirrhosis*
- Chronic lung disease, including asthma
High risk factors with immunocompromised
- Sickle cell disease, congenital and acquired asplenia
- Congenital immune system defects*
- Immunosuppressive therapies (steroids, chemotherapy, radiotherapy, HIV treatment, post-transplant therapies)*
- Hematopoietic stem cell transplantation (recipient)*
- Malignant neoplasms
- Nephrotic syndrome*
- Solid organ or islet transplant*
Other risk factors
- Smoking
- Alcoholism
- Illicit drug use
- Homelessness
- Communities with consistently high invasive rates
- Recent use of antibiotics
- Cough reflex dysfunction
- Malnutrition status
* Highest risk groups
Functional or anatomic asplenia increases the risk of invasive pneumococcal disease 50-fold. If elective splenectomy is planned, the patient should be vaccinated at least two weeks before surgery and at least two weeks after emergency splenectomy. Rates of invasive pneumococcal disease are also increasing in children from some racial and ethnic groups, including Alaska Natives, African Americans, and certain American Indian groups.
How many types of pneumococcal vaccines are there?
There are currently two types of pneumococcal vaccines: pneumococcal polysaccharide vaccine (PPSV) and pneumococcal conjugate vaccine (PCV), and each formulation contains different serotypes. The PPSV vaccine does not induce the production of memory B cells, while the PCV vaccines induce the production of memory B cells and provide long-lasting immunity.
History of pneumococcal vaccines
The first attempts at vaccination were based on the inoculation of heat-killed mixed pneumococcal serotypes against pneumococcal pneumonia in men working in gold mines in South Africa by the British physician Almroth Wright in the early 1900s.
With the introduction of penicillins in the 1940s, interest in pneumococcal vaccines waned; in fact, a systematic review of the ethology of pneumonia found only four publications on the subject between 1946 and 1970.
In the late 1960s, after many patients were still dying despite antibiotic treatment, renewed efforts were made to develop a polyvalent pneumococcal vaccine.
The first pneumococcal vaccine was licensed in the United States in 1977. This vaccine contained capsular polysaccharide antigens purified from 14 different pneumococcal species.
The new capsular polysaccharide vaccine PPSV23 (Pneumovax 23), based on the 23 most common serotypes causing the disease, was licensed in 1983 and replaced the 14-valent vaccine. PPSV23 was licensed in 1997 for people over 65 years of age and for people 19-64 years of age with chronic disease or in an at-risk group.
The main problem with PPSV is that it cannot be used to vaccinate infants and young children, who are at highest risk for pneumococcal disease. To overcome this problem, researchers at Wyeth, inspired by work on the H. influenza tib b meningitis vaccine, conjugated the capsular polysaccharides of the seven most common S. pneumoniae strains, opening a new chapter in pneumococcal vaccines.
The initial pneumococcal conjugate vaccine, PCV7 (Prevnar 7), was approved for use in the United States in 2000. Following the introduction of PCV7 into immunization programs, a study conducted in Northern California demonstrated a 95% reduction in the incidence of pneumococcal meningitis in fully vaccinated infants and greater than 97% efficacy against all invasive pneumococcal diseases.
The increasing incidence of disease caused by another strain, called serotype 19A, has raised awareness of the need to continue the development of pneumococcal vaccines, leading to the development of new PCVs covering strains 10, 13 and 15.
In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13) was licensed in the US. This vaccine contains serotypes 1, 3, 5, 6A, 7F and 19A in addition to the same 7 serotypes as PCV7.
PCV13 was first recommended in the childhood vaccination guidelines and then in the guidelines for people over 50 in 2011. In 2012, PCV13 + PPSV23 was approved for at-risk adults; in 2014, PCV13 + PPSV23 was approved for people 65 years and older; in 2021, PCV15 and PCV20 were approved for adults; in 2022, PCV15 was approved for children; and in 2023, PCV20 was approved for children.
What is the association between pneumococcal vaccines and antibiotic resistance?
Pneumococcal diseases are among vaccine-preventable diseases. Problems such as high mortality and risk of permanent sequelae, burden on the healthcare system and antibiotic resistance reveal the necessity of pneumococcal vaccines.
S. pneumoniae has gained resistance to many drugs over the years and has made the treatment of pneumococcal infections much more difficult. Prevention of the disease through vaccination is now more important than ever.
Previously highly responsive to penicillin, S. pneumoniae has now developed resistance to this and many other antibiotics. Overall, macrolide-resistant S. pneumoniae is the most concerning form of drug-resistant S. pneumoniae. In the USA, rates of macrolide-resistant S. pneumoniae are often 30% or higher, and macrolide failures have been reported in both clinical trials and case reports.
S. pneumoniae resistance to penicillin and other antibiotics used to be very common. After the introduction of PCV7, antibiotic resistance decreased and then began to increase again. Since the introduction of PCV13 in children in 2010, antibiotic-resistant pneumococcal infections have decreased significantly.
As serotypes and antibiotic resistance of S. pneumoniae strains vary between regions, each country should determine its own pneumococcal serotype diversity and antibiotic resistance profile.
Despite the problem of antibiotic resistance, which we briefly mentioned to draw attention to the importance of vaccines, antimicrobial prophylaxis is particularly recommended in some groups of patients. The most typical example is children under 5 years of age with functional or anatomical asplenia. The American Academy of Paediatrics typically recommends daily antimicrobial prophylaxis with oral penicillin V for these children. This should be continued for at least 1 year after splenectomy. Vaccination is also recommended.
Pneumococcal polysaccharide vaccine (PPSV)
PPV23 (Pneumovax 23) contains purified polysaccharide from the 23 most common capsular types of S. pneumoniae (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F). In PPSV 23, 12 serotypes of PCV 13 are already present.
Polysaccharides are T cell-independent antigens and infants under 2 years of age respond poorly to them, probably due to their immature immune systems. PPSV 23 is licensed for use in children over 2 years of age and adults.
PPSV is also recommended for people over 65 years of age and those with underlying health conditions, but specific recommendations for PPV23 may vary depending on the country and guidelines issued by national health authorities or organisations.
Using a case-control design, Shapiro et al. showed that protection by PPSV23 in young adults exceeded 90% at 3 years and remained >85% for 5 years of follow-up. However, protection decreased with each decade of age, and no protection was observed in the oldest group five years after vaccination.
The most commonly reported adverse reactions in pre-approval PPSV23 studies were local reactions, headache, fatigue and myalgia. These reactions usually resolved within 48 hours. In people aged 65 years and older who participated in the study, vaccine-related systemic adverse reactions were more common following the second dose compared to the first dose.
What are the general rules for the administration of pneumococcal vaccines?
- PCV and PPSV23 should not be given at the same visit.
- Conjugate vaccines and polysaccharide vaccines are NOT interchangeable. Although the polysaccharide vaccine is effective against a wider range of serotypes, it has different immunogenic properties and is usually offered in addition to a series of conjugate vaccines, not as a replacement for such a series.
- The administration of the conjugate vaccine is independent of the polysaccharide vaccine and should never be omitted or delayed.
- In general, PCV vaccines can be used interchangeably to complete an immunisation series. For example, a series started with PCV13 can be continued with PCV15 and vice versa.
- If both are needed, PCV should be given first.
- A single dose of PCV is recommended for adults (if there are no additional comorbidities).
- ≥65 years of age should receive a single dose of PPSV23. If an immunocompromised person aged 65 years or older has received PPV23 on or after their 65th birthday, they do not need to receive another dose of PPV23 5 years later. This is because the immune response to the vaccine decreases as people get older.
- In cases where PPSV23 is recommended, it is recommended no more than 3 times in adult life, with at least 5 years between doses. The last dose is recommended after the age of 65.
- If PPSV23 has been given, PCV should be given at least 1 year later.
- If PCV has been given, PPSV23 should be given at least 8 weeks later.
- The new recommendations for unvaccinated persons are that adults aged 19-64 years with any underlying medical condition (comorbidities, high-risk conditions or immunocompromised) and all persons aged 65 years and older should receive one dose of PCV20 alone or one dose of PCV15 followed by PPSV23 one year later.
- PCV20 is preferred over PCV15 and PCV15 over PCV13.
- PCV is administered as a single dose in the adult age group, except in bone marrow transplant patients. In cases of severe immunosuppression, cerebrospinal fluid leakage, cochlear implant, asplenia, where antibody titres need to be raised rapidly, 8 weeks should elapse between PCV and PPSV vaccination.
- Hematopoietic stem cell transplant recipients, regardless of age, should begin pneumococcal vaccination 3 to 9 months after transplant with 3 doses of approved PCV administered at least 4 weeks apart, followed by 1 dose of PPSV23 12 to 18 months after transplant (at least 6 months after the last dose of PCV). Hematopoietic stem cell transplant recipients older than 2 years of age should receive an additional booster dose of PPSV23 administered 1 year after the first dose of PPSV23.
- There should be at least 2 weeks between cancer chemotherapy or immunosuppressive treatment and vaccination. Vaccination should not be given during these interventions. If PPV23 has been given during chemotherapy or radiotherapy, another dose of vaccine is recommended 3 months after treatment.
- Vaccination should be avoided in people with a moderate or severe acute illness. In cases of mild illness with or without fever, vaccination may continue as planned.
- Both types of vaccine are administered as 0.5 ml IM. The dose for all licensed products is 0.5 mL. Conjugate vaccines should be given intramuscularly (IM). Polysaccharide vaccines can be administered intramuscularly (IM) or subcutaneously (SC).
- Contraindications: Severe allergic reaction to the vaccine or any of its components. Conjugated vaccines should not be administered in patients with a history of severe allergic reaction to TDaP vaccines.
What are the general guidelines for pneumococcal vaccination in children?
In children under 2 years of age, routine vaccination is 1 dose of PCV15 or PCV20 at 2 months, 4 months, 6 months and 12 to 15 months of age.
Healthy children aged 2-5 years with an incomplete PCV series should receive 1 dose of PCV.
PCV15 or PCV20 can be used if PCV is indicated. For children without risk factors, PCV20 is not indicated if they have received 4 doses of PCV13 or PCV15 or another complete PCV series appropriate for their age.
Vaccination with a 4-dose PCV programme (3+1) is recommended for children with underlying medical conditions associated with a high risk of invasive pneumococcal disease. Additional immunisation with PPSV23 is recommended at 24 months of age, while those at highest risk should receive an additional booster dose.
Premature infants with stable clinical conditions should be vaccinated with an licensed PCV at the same chronological age and according to the same schedule as term infants. Hospitalised infants with a birth weight of less than 1500 grams should receive continuous cardiac and respiratory monitoring for 48 hours after the first dose.
What is Capvaxive (PCV21)?
The FDA approved Merck's 21-valent pneumococcal conjugate vaccine Capvaxive on 17 June 2024 for the prevention of invasive pneumococcal disease and pneumococcal pneumonia in adults aged 18 years and older.
According to Merck, it is the first pneumococcal conjugate vaccine designed specifically for adults and aims to provide broader protection than existing vaccines on the market.
Walter Orenstein, from Emory University in Atlanta, said in a statement: "Complications from invasive pneumococcal disease can lead to hospitalisation, organ damage and even death. Many cases of adult disease are caused by serotypes that are not included in other licensed pneumococcal conjugate vaccines.”
According to the CDC, the vaccine has the potential to reduce 150,000 hospitalisations and 41,000 deaths from pneumococcal pneumonia in the US each year.
Who should receive Capvaxive?
The Advisory Committee on Immunisation Practices (ACIP) has decided to recommend a single dose of PCV21 (CAPVAXIVE), specifically for
- Adults aged 65 years and older who have never received pneumococcal conjugate vaccine or whose vaccination history is unknown.
- Adults aged 19-64 years with certain underlying medical conditions or other risk factors who have not received PCV or whose vaccination history is unknown.
- Adults aged 19 years and older who have started the pneumococcal vaccine series with PCV13 but have not received all recommended doses of PPSV23.
In addition, shared clinical decision making is recommended for the use of an additional dose of CAPVAXIVE in adults aged 65 years and older who have completed the vaccination series with both PCV13 and PPSV23.
How does PCV21 differ from other PCVs, especially PCV20?
The vaccine contains eight unique serotypes not covered by other existing vaccines (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B). In addition, PCV21 covers 11 unique serotypes not found in PCV20. So Capvaxive is not just PCV 20 plus one.
In its review of the evidence, ACIP stated that PCV 21 provides better coverage of serotypes that cause invasive pneumococcal disease in adults compared to PCV 20.
According to CDC data from 2018-2021, the serotypes covered by CAPVAXIVE are responsible for more cases of invasive pneumococcal disease in adults compared to PCV20. Since most cases in adults are caused by subtypes not covered by other FDA-approved pneumococcal vaccines, the PCV21 vaccine can be considered an important new weapon.
According to Merck's statement, which cites CDC data, the 21 strains in Merck's vaccine account for about 85 percent of cases of invasive pneumococcal disease in adults aged 65 and older. Meanwhile, Pfizer's Prevnar targets strains that account for only about 51% of cases in this age group, according to the same CDC data.
Are there any disadvantages to using PCV21 compared to other PCVs?
PCV21 does not include serotype 4, which is an important cause of invasive pneumococcal disease in some populations. The risk of invasive disease due to serotype 4 is 100-300 times higher in homeless adults living in poor conditions. Another group at high risk of serotype 4 are Alaska Natives, who are 88 times more likely to develop invasive disease.
Fortunately, serotype 4 is covered by other pneumococcal vaccines, including PCV 15, PCV 20 and PPSV 23; for these patients, PCV20 is probably a better conjugate vaccine option than PCV21.
What is the safety profile of the Capvaxive vaccine?
Merck has reported that the vaccine has a comparable safety profile to other available vaccines, including PCV20, PCV15 and PPSV23.
The most commonly reported adverse reactions in people aged 18-49 years receiving PCV21 were injection site pain (73%), erythema (14%) and swelling (13%); fatigue (36%); headache (28%) and myalgia (16%).
In adults aged 50 years and older, injection site pain (41%), fatigue (20%) and headache (11%) were reported.
PCV21 should not be given to anyone with a history of severe allergic reactions to any of its components or to diphtheria toxoid.
Last message
With the routine use of conjugated pneumococcal vaccines in many countries, the incidence of invasive pneumococcal disease has decreased significantly. Even outside the age groups targeted by the vaccination programme, some invasive pneumococcal diseases caused by vaccine serotypes have virtually disappeared, suggesting the concept of community immunity.
Although the burden of pneumococcal disease has decreased significantly in age groups vaccinated with paediatric conjugate vaccines, pneumococcal disease remains an important cause of morbidity, particularly in adults. Vaccination plays a very important role in reducing the rate of invasive pneumococcal infections, which can affect all organ systems and have a high mortality rate.
The development of PCVs is a major benefit to global health, with an estimated 7 million deaths averted by 2030, allowing us to look to the future with hope.
Despite evidence highlighting the benefit of pneumococcal vaccination, only 51% of the global infant population has received their last dose, and only 19% of this proportion is in the WHO Western Pacific Region. In addition, by the end of 2021, 46 out of 194 WHO Member States still had not included PCV in their national immunization programmes. Without routine immunization, pneumococcal disease will continue to cause morbidity and mortality worldwide.
To protect adults and the elderly, it is still debated whether children should be vaccinated with conjugate vaccines and rely on herd immunity, or whether these vaccines should be used directly in adults. Vaccine residual disease and the emergence of non-vaccine serotypes are important issues. As children are the main reservoir for pneumococci, the use of these vaccines in children can both increase the risk of colonization with non-vaccine serotypes and lead to new serotype diseases. The ideal solution is to develop vaccines that are effective against all pneumococcal serotypes.
In short, the one thing we can say with certainty about the future of pneumococcal vaccines is that the story continues. In addition to PCV21, which is the subject of this paper, pneumococcal vaccines with even more serotypes, including 25-valent and 31-valent, are in development.
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