Adult vaccination

Abstract

Vaccination of children has had a major impact on the morbidity and mortality of many infectious diseases globally. However, with age, immune responses to vaccines can be less robust, which can be further enhanced by underlying diseases that are common in the older adult. In many countries around the globe booster vaccinations against diphtheria, tetanus, and pertussis are recommended for adults. For the older adult, vaccination against pneumococcal diseases, influenza and herpes zoster are also recommended. Despite these recommendations, the widespread use of these vaccines in the adult population clearly lags behind the vaccine uptake and successes documented for pediatric vaccination programs. Furthermore, extensive and sometimes inappropriate use of antibiotics have fostered the emergence of antibiotic-resistant bacteria (e.g., methicillin resistant Staphylococcus aureus (MRSA)) as well as increased susceptibility in the elderly to bacterial species such as Clostridium difficile. Infectious diseases remain an important unmet medical need and new concepts to successfully implement vaccination of adults are urgently needed.

Keywords: :

• vaccine
• infectious disease
• pneumococcal disease
• Staphylococcus aureus
• Clostridium difficile

Importance of Adult/Elderly Vaccination

Vaccines have provided a more positive impact on public health globally than any other medical intervention. The majority of vaccines developed to date have targeted the pediatric population. Vaccine uptake for this population overall is usually well above 90% in many countries and is highly supported by vast national and international collaborative initiatives to ensure that all children have appropriate access to life-saving vaccines. Both the US-based Vaccines for Children (VFC) program and the global WHO-sponsored Global Vaccine Action Plan (GVAP) are examples of frameworks designed to prevent millions of deaths through more equitable access to existing vaccines. The CDC recently reported that for children born during 1994–2013, vaccination will prevent an estimated 21 million hospitalizations and 732 000 deaths throughout their lifetime. Together, this would result in a savings of $1.38 trillion in total costs to society.¹ Since life expectancy has been dramatically increased by the provision of clean water, vaccines, and other factors, the global aging population continues to grow. For example, it is expected that the number of individuals >80 y of age will triple over the next 50 y² and approximately 20% of the global population will be elderly (>65 y of age) by 2050 (Fig. 1).^3,4 In this context, it is important to realize that the human immune system increasingly becomes less efficient in fighting infections or responding to vaccines. Therefore, taking advantage of existing adult vaccines earlier in adulthood and developing vaccination strategies that can overcome weakened immune systems is of fundamental importance to provide the appropriate protection for the aging adult population.

Figure 1. Projected future growth of the older population. This chart shows the percent of the population 65 and older increasing from 4 percent in 1900 to 12 percent in 2000 and projected to be 20 percent in 2050. It also shows the percent of the population 85 and older increasing from 0.2 percent in 1900 to 1.5 percent in 2000 and projected to be 4.3 percent in 2050. Graph is adapted from the Administration on Ageing, Health and Human Services.

Current Adult Vaccination Trends

Today’s vaccines recommended for adults can be divided into those for the general population and those indicated for individuals with specific risk factors such as pre-existing diseases (e.g., chronic lung or heart disease, diabetes mellitus), compromised immune system, travel, or potential occupational risks, such as exposure of healthcare workers. Age based recommendations have been developed based on periods of life in which there is increased risk of contracting infectious diseases. As an example, the majority of pneumococcal infections and invasive pneumococcal diseases (IPD) can be successfully prevented in infants and young children by use of pneumococcal conjugate vaccines in the very young.^1,5,6 Nevertheless, this leaves individuals 50 y of age and older at risk and this risk increases with age^7,8 (http://apps.who.int/healthinfo/statistics/mortality/whodpms, Accessed March 5, 2014). In Western countries regular booster doses against tetanus, diphtheria, and often pertussis are indicated for the general adult population.^9,10 Influenza vaccination is currently administered annually and is recommended for all adults, though in some countries it is only indicated for adults with specified risk factors.¹¹ In addition, vaccination against pneumococcal diseases and zoster are recommended for adults at increased risk and the elderly.

Globally, the most common vaccine preventable cause of death results from infection with Streptococcus pneumoniae. According to WHO estimates, of the 1.6 million deaths due to pneumococcus annually, roughly half occur in children < 5 y and half in the elderly (WHO 2004 Global Immunization Data. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed June 7, 2009). Although the 23-valent polysaccharide pneumococcal vaccine (PPV23) is indicated for prevention of IPD there is conflicting evidence that the vaccine can prevent pneumococcal non-bacteremic pneumonia, which is the most common and life-threatening manifestation of invasive pneumococcal infection in adults.^12-14 Moreover, effectiveness of the PPV23 vaccine against pneumococcal community acquired pneumonia (CAP) with bacteremia as well as other types of IPD are limited to an overall 24% with a duration of protection of only 3–5 y.¹⁵ There is also the concern that the vaccine could possibly induce B-cell depletion and hypo-responsiveness, which may in fact increase the risk for IPD particularly in immunocompromised subjects.^16-18 These concerns in turn have affected uptake of the vaccine in adults.¹⁹

The pneumococcal polysaccharide conjugate vaccine, PCV13, recently licensed for the elderly, is a qualitatively different vaccine aimed to overcome the challenges seen with PPV23. Conjugation of the pneumococcal polysaccharides to the protein carrier CRM197 (non-toxic mutant form of diphtheria toxin) in PCV13 drives a T-cell-dependent immune response, in contrast to the T-independent response elicited by PPV23. A T-cell dependent response is particularly important in infants and older adults whose immune systems have either not fully matured or are entering immunosenescence, respectively. The biological differences with PCV13 induced by T-cells include reduction of colonization with the pneumococcus, IgG responses in infants (as compared with IgM only responses to PPV23), higher antibody responses against most vaccine-serotypes as well as induction of immunological B-cell memory, which is not seen with PPV23. Clinical studies with PCV13, including comparisons between PCV13 and PPV23, have shown the serological superiority of PCV13 for most serotypes shared by the two vaccines in more than 8000 subjects. They have also demonstrated that PCV13 responses, unlike PPV23 responses, can be boosted thus providing an important tool for continued protection against this important pathogen in the older adult.²⁰ In countries with a high PCV13 uptake for infants herd protection has been observed for the older adult population^21,22; however there remains sufficient disease burden^23-25 to drive the need to immunize not only infants but the elderly as well. For the first time ever with a pneumococcal vaccine, PCV13 has shown efficacy against non-bacteremic pneumonia in a double blind randomized clinical trial in a general population of subjects ≥ 65 y.²³

CAPiTA (Community-acquired Pneumonia Immunization Trial in Adults) was a Phase 4 trial to support post-approval commitments of demonstrating vaccine efficacy against all vaccine type pneumococcal community acquired pneumonia (VT-CAP) and also against non-bacteremic VT-CAP in individuals 65 y and older. The CAPiTA trial successfully demonstrated a reduction of VT-CAP cases in PCV13 vaccinated individuals and protection that lasted at least four years.²³ These results offer an important example of broadening the indication of a currently licensed vaccine beyond the pediatric population to provide the tools to ultimately reduce morbidity and mortality in the older adult.

Adult Vaccines: The New Horizon

As populations age, individuals have more frequent contact with the healthcare system and many live in long-term care settings. This puts older adults at increased risk of certain bacterial diseases. Weakened immunity and increases in antibiotic usage have resulted in rises of disease caused by Staphylococcus aureus and Clostridium difficile.^26,27 No licensed vaccine currently exists to prevent infections from either of these pathogens; however several vaccines are in development.^28-30

Both pathogens are Gram positive organisms that can cause disease with considerable consequences for the patient. S. aureus infections range from relatively mild skin infections to life-threatening invasive disease and pneumonia.³¹ Antibiotic resistance has made S. aureus infections more difficult to treat and subjects with an infection that is resistant to antibiotics have a worse outcome and are more costly to treat.^32,33 C. difficile is a spore-forming bacterium that resides in the gut and is the main cause of nosocomial infectious diarrhea in industrialized countries.³⁴ In the last decade, hyper virulent strains have become endemic in the hospital setting making C. difficile-associated disease (CDAD) an emerging and significant healthcare problem.³⁵ Similar to S. aureus, this is potentiated by an increased use of antibiotics, growing antibiotic resistance, and additionally due to the difficult elimination of C. difficile spores that can survive harsh environments. Normal gut flora provide natural resistance to C. difficile; however antibiotic treatment can disrupt this natural defense leading to increased infection and disease risk.³⁶ Once the organism colonizes the gut it produces toxins that cause the patient to develop severe gastroenteritis, diarrhea and can irreversibly damage the intestines. Together, S. aureus and C. difficile infections are associated with increased healthcare costs amounting to many billions of dollars even with application of good infection control practices.^37-39 To prevent diseases caused by these organisms, distinct approaches are required.

S. aureus has a wide arsenal of virulence factors that it deploys to cause disease.^40,41 While many pre-clinical studies were designed to identify potential vaccine targets,⁴² only two vaccines have been tested in efficacy trials to date.^43,44 These vaccines had different compositions, were tested in different target populations, and neither was efficacious in preventing S. aureus disease. The drawback of both vaccines was that they targeted single antigens. Now with a deeper understanding of how S. aureus causes disease,⁴¹ it has become clear that a vaccine against this complex pathogen should target multiple virulence mechanisms.^45-47 Three multi-antigen prophylactic vaccines are currently being evaluated in Phase 1/2 clinical trials. SA4Ag is a vaccine being developed by Pfizer and is composed of capsular polysaccharides (type 5 and type 8), Clumping factor A (ClfA) and Manganese transporter C (MntC).⁴¹S. aureus disease-causing strains can either express type 5 or type 8 capsular polysaccharide, which forms a shield in vivo to protect the bacterium from host immune responses. Anti-capsular polysaccharide antibodies thwart this defense mechanism by enabling the bacteria to be killed by opsonophagocytosis.⁴⁸ ClfA is a virulence factor that facilitates the binding of S. aureus to fibrinogen early during the infectious process.⁴⁰ Active vaccination with ClfA elicits anti-ClfA antibodies that block the binding of S. aureus to fibrinogen.⁴⁹ The fourth component, MntC, is required to import manganese that is used by S. aureus to neutralize the reactive oxygen species that neutrophils produce to kill the bacterium.⁵⁰ The second vaccine is being developed by Novartis and is composed of a combination of proteins associated with iron acquisition,⁵¹ intracellular invasion⁵² and host binding proteins.⁵³ Glaxo Smith Kline is also developing a multi-antigen vaccine that includes capsular polysaccharide conjugates, ClfA and alpha toxin (ref. 64). Though there are promising early clinical results regarding how these vaccines perform in humans, controversy regarding the actual mechanism of immune protection remains and will not be resolved until efficacy is demonstrated in well controlled clinical trials.²⁹

C. difficile produces two large exotoxins, A and B (TcdA and TcdB), that are primarily responsible for causing CDAD symptoms and are therefore of considerable interest as vaccine antigens.⁵⁴ A prophylactic vaccine capable of eliciting toxin-neutralizing antibodies is a key approach for the C. difficile vaccines in development.⁵⁵ Toxins A and B were the first antigens tested⁵⁶ and continue to be evaluated using various approaches. Three toxin-based vaccine approaches are currently undergoing clinical testing for the primary prevention of C. difficile infection in adults and elderly. The first, developed by Sanofi Pasteur, uses purified toxins that are rendered inactive by formalin treatment.^28,57 The second approach developed by Valneva is a recombinant vaccine that uses truncated forms of toxin A and B.⁵⁸ The third approach is being developed by Pfizer⁵⁹ and utilizes ClosTron technology to stably express genetically inactivated toxoids from a toxin deficient C. difficile strain. To further control for residual toxicity, the genetically modified toxoids are subjected to a mild chemical inactivation step. This was developed to preserve determinants on the toxins that are important to elicit broad toxin neutralizing antibodies and that are destroyed by formaldehyde treatment.³⁰ Both toxoid-based and recombinant vaccines have been shown to induce toxin-neutralizing activity in healthy adults, including individuals 65 y of age or greater.^57,58 Older adults entering long-term care facilities or individuals with chronic health problems requiring prolonged antibiotic exposure could significantly benefit from a C. difficile vaccine. The challenge will be to elicit a rapid and prolonged protective immune response in a population undergoing immunosenescence.

Challenges and Future Prospects

As evidenced by the two examples above, many important vaccine initiatives are underway to protect the growing population of older adults. However, one of the ever present challenges is that vaccine uptake in adults remains low.^60,61 For example, just 20% of individuals > 60 y of age have received the herpes zoster (Shingles) vaccine⁶² even though the vaccine clearly protects against severe post-herpetic neuralgia, the severe pain associated with re-activation of the virus in older individuals.^63,64 This low vaccine uptake is encumbered in part by the current passively administered risk-based vaccination recommendation strategy, slow societal acceptance and lack of commitment from national health systems to fully implement recommended vaccines.

The current challenge that remains is to develop vaccination programs for adults that are as far reaching and effective as programs for children. To achieve this, a number of policies, public education campaigns and operational frameworks need to be put into place. This begins with clearly defined and publicly accepted vaccination goals regarding vaccine uptake and expected morbidity and mortality reduction in a defined time frame. Second, there must be a single unified plan, in contrast to what is common in most European Union (EU) countries, where plans are often designed not by country but by individual regions. Vaccines that have long been included in the immunization regimen have been found to have a more homogeneous schedule across the EU, whereas newer vaccines varied in the recommended schedule, dose, and target population.⁶⁵ Third, there must be a simple yet effective means to provide educational support for healthcare providers to implement such a program, including funding and advertising by unbiased local and national government agencies and health insurance organizations. This can translate into both better informed patients who may request immunization, as well as healthcare providers conducting more routine assessments of patient’s immunization status. A fourth and critical piece is to implement a process for annual monitoring of vaccine uptake and the impact of the vaccine with regard to reduced morbidity and mortality. Such programs have been extremely effective, wherever implemented for children,¹ and will benefit vaccine initiatives for the elderly population.

The availability of new vaccines and vaccines with new indications (e.g., PCV13, Tdap, zoster) targeted for adults and the elderly population will provide huge health benefits by protecting against many important infectious diseases. As the size of the elderly population continues to grow, the need for new vaccines to appropriately protect against prevailing infectious diseases (S. aureus, C. difficile, influenza, and respiratory syncytial virus) will remain an important need and focus for future vaccine development. Newer technologies and more potent adjuvants will need to be explored to overcome increasing immunosenescence in an aging population. In summary, based on the experience from pediatric vaccination programs, a continuing concerted effort by vaccine manufacturers, healthcare providers, and health policy makers to expand the adult vaccine repertoire and to enhance vaccine uptake will lead to improved general health and more importantly to a better quality of life for the elderly.

Abbreviations:
PPV23	=	23-valent pneumococcal polysaccharide vaccine
PCV13	=	pneumococcal conjugate vaccine
IPD	=	invasive pneumococcal disease
CAPiTA	=	Community Acquired Pneumonia Immunization Trial in Adults
VT-CAP	=	Vaccine type-community acquired pneumonia
CDAD	=	Clostridium difficile-associated disease

Disclosure of Potential Conflicts of Interest

All authors are employees of Pfizer and may own Pfizer stock.

Acknowledgements

The authors would like to thank the following employees of Pfizer for their insightful comments for this manuscript (Emilio Emini, Ingrid Scully and Paul Liberator), and for documentation assistance (Christina Regan and Jessica Brigham).