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- Published: 09 February 2024
Exploring the future adult vaccine landscape—crowded schedules and new dynamics
- Charles H. Jones ORCID: orcid.org/0009-0004-0368-6463 1 ,
- Matthew P. Jenkins 1 ,
- B. Adam Williams 1 ,
- Verna L. Welch 1 &
- Jane M. True 1
npj Vaccines volume 9 , Article number: 27 ( 2024 ) Cite this article
- Infectious diseases
- RNA vaccines
Amidst the backdrop of the COVID-19 pandemic, vaccine innovation has garnered significant attention, but this field was already on the cusp of a groundbreaking renaissance. Propelling these advancements are scientific and technological breakthroughs, alongside a growing understanding of the societal and economic boons vaccines offer, particularly for non-pediatric populations like adults and the immunocompromised. In a departure from previous decades where vaccine launches could be seamlessly integrated into existing processes, we anticipate potentially than 100 novel, risk-adjusted product launches over the next 10 years in the adult vaccine market, primarily addressing new indications. However, this segment is infamous for its challenges: low uptake, funding shortfalls, and operational hurdles linked to delivery and administration. To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market. This article aims to provide that fresh perspective, offering a detailed analysis of the anticipated number of adult vaccine approvals by category and exploring how our understanding of barriers to adult vaccine uptake might evolve. We incorporated pertinent insights from external stakeholder interviews, spotlighting shifting preferences, perceptions, priorities, and decision-making criteria. Consequently, this article aspires to serve as a pivotal starting point for industry participants, equipping them with the knowledge to skillfully navigate the anticipated surge in both volume and complexity.
As the adult vaccine landscape rapidly evolves, we find ourselves at a crossroad where addressing the status quo of immunization efforts is no longer an option but a necessity. The COVID-19 pandemic served as a stark wake-up call, shattering the comforting illusion of “there is always next year”—a sentiment that echoes the preludes to the 2008 financial crash. This global health crisis exposed the fragmented nature of our adult vaccine infrastructure on both domestic and international fronts, revealing a system that is wholly unprepared for the impending rapid growth in the adult vaccine market. Leaders within the pharmaceutical industry, however, view the challenges within the adult vaccine industry as catalysts for transformation—a chance to reshape the adult vaccine landscape and contribute to a modern-day renaissance that promises improved immunization outcomes in the years to come.
The ongoing and accelerating transformation in adult vaccines is expected to be propelled by the rise of RNA technology, thrusting us into a new era of digital vaccines 1 . Unlike their traditional biologic counterparts, RNA-based solutions are not constrained by the same production process for varying antigens sequences 1 . Instead, the manufacturing process remains largely the same, with only variations in the antigen sequence encoded in the RNA vaccine. This opens the door to conceptualize innovative vaccine designs using a single manufacturing process—a departure from the conventional wisdom that “the process is the product,” and a giant leap forward for future vaccine design and development.
The timing of this vaccine revolution is critical. As the world’s population ages, the call for more potent vaccines to safeguard health and wellness rises (Fig. 1A ). Currently in the United States, the healthy life expectancy (HALE) is only 66 years, despite it spending more than any other G20 nation on health care (Fig. 1B ). However, the older demographics are increasingly embracing self-care and healthy aging, thereby fueling demand for healthcare products that promote longevity, such as vaccines against infectious diseases that pose significant risk to these populations 2 . This need is further driven by the impact infectious diseases have on the economy. Vaccine-preventable diseases (VPDs) account for an estimated 8 to 10 million disease cases in the U.S. alone, resulting in up to $34.9 billion in annual societal costs 3 . However, current vaccination rates in the U.S. for most of these diseases fall significantly short of the Healthy People 2030 targets 4 , even as the burden of infectious diseases is poised to escalate (Fig. 1C ). Increasing vaccination rates to achieve these targets could result, over the course of 30 years, in an additional 33 million averted disease cases, a saving of $96 billion in costs, and nearly $83 billion in incremental vaccination costs 5 . The impact of VPDs also goes beyond measurable economic impacts as older adults play an invaluable role in the informal economy, offering childcare, and financial and emotional support 6 . Such contributions cannot be quantified through economic analyses alone.
A Depicts the growth of the U.S. population segment aged 65 years old and above from 2022 to 2040. Data for 2022 was sourced from the U.S. Census Bureau’s annual estimates (U.S. Census Bureau, Population Division, June 2023), while future projections were obtained from the IHME’s Global Fertility, Mortality, Migration, and Population Forecasts 2017–2100 (IHME, 2020). B Highlights the relationship between primary health care funding schemes in select G20 countries (excluding Saudi Arabia and Turkey due to lack of data) and life expectancy at birth and HALE at birth. Health expenditure data was sourced from WHO’s Global Health Expenditure Database and Life expectancy data was retrieved from the Global Health Observatory Data Repository for 2019. C Illustrates the projected disease burden for age groups 50–69 years and 80+ years, with bubble size denoting death per 100,000. Percentages correspond to an increase in area. Data is derived from the Global Burden of Disease Study 2016 (IHME, 2018). Note: The age group 70–79 is not represented due to unavailability of data.
Technical challenges associated with developing adult vaccines add another layer of complexity and can pose significant barriers. Future vaccines will need to be tailored to different risk groups for optimal efficacy, as immune responses vary across adult populations 7 . This is especially true for older adults, who often exhibit weaker immune responses due to immunosenescence 8 . Therefore, vaccines for older adults may require higher doses or specially designed adjuvants to compensate for this 9 . Diseases prevalent across various age groups could be driven by different strains of the same pathogen, leading to a balancing act in vaccine design. Pneumococcal disease perfectly illustrates this point where the most significant serotypes vary between different age groups 10 . As a result, vaccine makers might prefer to include those serotypes that are most relevant to pediatric populations. This approach was demonstrated in the Shared Clinical Decision-Making (SCDM) decision in 2019, where the protection from pediatric vaccination was considered sufficient for at-risk adults 11 . These complexities have driven prioritization of certain age groups, primarily shifting focus to younger populations due to high vaccine efficacy, lower social contact, and widespread adherence to nonpharmaceutical interventions 12 .
To better understand the evolving adult vaccine market, we conducted a market research study, using the U.S. as a pivotal case study. Through collaboration with key stakeholders from various sectors, we established a foundational understanding of the current and future landscape that will pave the way for subsequent assessments specific to countries or regions. Our research reveals crucial insights into the challenges and weakness of the adult vaccine market which, if not addressed, may quickly become overwhelmed in the face of an evolving and expanding industry. Equipped with this knowledge, we aim to change “there is always next year” from a complacent phrase to an urgent call for innovation, fostering a healthier future with enhanced access, affordability, and awareness for adult vaccines.
Impending adult vaccine market evolution and growth
Historically, pediatric vaccines have been prioritized over vaccines designed specifically for adults. In fact, the first vaccine approved following the formation of U.S. Food and Drug Administration (FDA) was the diphtheria pediatric vaccine in the early 1920’s, nearly 20 years before the approval of the first adult vaccine for influenza in 1945 13 . This bias was justified in the mid-twentieth century, which saw a surge in the adolescent population due to improved healthcare and the baby-boom following World War II 14 . The vulnerability of this population to common infectious diseases, such as measles, mumps, and rubella, necessitated a robust pediatric immunization program. Other factors, such as the homogeneity of the pediatric population and the frequency at which they interact with the healthcare system 15 , have all led to the development of a strong pediatric immunization program in the U.S. today, consisting of clear guidelines, well-defined immunization schedules, and school entry requirements. Together, these factors have contributed to a vaccination rate among school-aged children of 90% 15 . In contrast, adult vaccines often face challenges such as limited awareness, accessibility, affordability, and vaccine hesitancy, which has resulted in vaccination rates that range from 20 to 62% 16 .
Despite these challenges, the adult vaccine market is experiencing rapid expansion, with a diverse range of anticipated products targeting diseases such as influenza, pneumococcal disease, herpes zoster (Zoster), hepatitis, and human papillomavirus (HPV) (Supplementary Fig. 1 ). This market, excluding pediatric specific vaccines, was valued at $19.48 billion in 2022 and is projected to reach $27.65 billion by 2028, reflecting a compound annual growth rate (CAGR) of 6.1% 17 . Its growth trajectory is fueled by the increasing prevalence of VPDs in adults, technological advancements like RNA vaccines, and a heightened focus on preventative healthcare.
Over the next decade, we anticipate a tripling in the number of approved vaccine products globally. Today, there are 35 products available for 13 disease areas. Over the next 10 years, we foresee between 100-120 risk-adjusted products (risk-adjusted using probability of technical and regulatory success [PTRS] values by stage of development) designed to protect against 40 different disease areas (Supplementary Fig. 1 ). Currently, our arsenal of vaccines is primarily divided into two main disease categories: those targeting well-known diseases like influenza, pneumonia, shingles, and COVID-19, and those designed for travel or endemic diseases like hepatitis B, Ebola yellow fever, tick-borne encephalitis, and Japanese Encephalitis. Looking towards the future, we can expect these categories to expand to include nosocomial vaccines, targeting infections acquired in healthcare settings like Clostridioides difficile ( C. diff ) and Staphylococcus aureus (Staph A). Furthermore, vaccines for diseases with high unmet needs, such as human immunodeficiency virus (HIV), may enter the adult vaccine landscape over the next 10 years.
In addition to expanded vaccine offerings, we also anticipate growing competition, with four historical leaders in the field (GlaxoSmithKline, Merck, Pfizer, and Sanofi) making significant advancements. However, it should be noted that the COVID-19 pandemic has likely reshuffled the adult vaccine landscape 18 , which has become one of the most competitive spaces in pharma. There has been increased pressure from both new entrants with differentiated technology platforms (such as Moderna’s mRNA portfolio and Dynavax’s adjuvant offering) and low-margin, high-volume global players (such as Serum Institute of India, Bharat Biotech, and Sinovac) 18 . Additionally, as best-in-class products likely will not be enough to capture the market, manufacturers are expected to distinguish themselves through differentiated portfolio offerings, rather than individual products 18 .
With the increasing number of adult vaccines entering the market, adult vaccine schedules are expected to undergo substantial expansion over the next decade (Supplementary Fig. 2 ). The current Advisory Committee on Immunization Practices (ACIP) adult vaccine schedule recommends that individuals aged 18 and above receive vaccines for influenza and COVID-19. It is also recommended that adults aged 50 and above get the Zoster vaccine, while those aged 65 and above are recommended pneumococcal vaccines. Moreover, both vaccines are recommended for adults aged 18 and older who have compromised immune systems. Those under 65 are recommended to get vaccinated against hepatitis B. Recently, two new RSV vaccines have been approved and may be considered for adults aged 60 and older through the process of shared clinical decision-making, as per SCDM guidelines. Looking forward to the next 10 years, we foresee most new vaccines being specifically developed for certain high-risk groups, irrespective of their age. For example, C. diff vaccines may be recommended for those aged 65 and above that are admitted to a hospital or long-term care facilities. We anticipate that COVID-19 and RSV vaccines will begin to mirror the pattern seen with the influenza vaccine, possibly evolving into seasonal vaccines 19 , 20 , 21 . This suggests that adults may be recommended to receive these vaccines annually, typically within a three-month window, assuming current seasonal vaccination behavior (agnostic of potential recommendation).
The possibility of a surge in seasonal vaccines could set the stage for a scenario where other, non-seasonal vaccines might find themselves being administered over a compressed three-month period. This potential phenomenon, termed forced seasonality, could pave the way for a convergence of campaigns for new vaccines with those of seasonal vaccines, instigated by the necessity to co-administer them to boost uptake. Such an alignment could pose substantial challenges for immunizers and vaccination delivery sites as they grapple with the task of accommodating new patients and vaccines within a more limited timeframe.
While forced seasonality has not yet burdened the immunization infrastructure, it may in the future as the adult vaccine market expands. In fact, if current vaccination rates are held constant, the total annual volume for adult vaccines will surpass 500 million doses dispensed in the U.S. alone by 2032 (Fig. 2A ). This estimate accounts for the risk-adjusted products expected to enter the market in the next 10 years, as well as their dosing regimens. Should this occur, this would be a considerable leap from the current 200 million doses administered annually. To put this into perspective, the global influenza vaccine market stands at approximately 600 million doses per year 22 . Assuming forced seasonality as well as current vaccination trends and behaviors in the U.S., we will find ourselves needing to process a volume equivalent to the entire global influenza vaccine market within the U.S. in a three-month span.
A Assessment of the projected future vaccine volume expansion in the U.S., by vaccine category, compared with current and pre-pandemic levels. Notable recent and anticipated vaccine launches are called out. The box around COVID indicates that this launch has already occurred. A more comprehensive representation of anticipated vaccine launches can be found in Supplementary Fig. 1 . B Weekly COVID-19 Vaccine Administrations and Productivity in 2022 and Projections for 2032. This figure presents the number of COVID-19 vaccine doses administered weekly throughout 2022. This data was obtained from the CDC’s COVID Data Tracker. Weekly productivity, represented as millions of doses administered per week, during the peak vaccination season (September to December) for actual 2022 COVID-19 vaccine administrations and 2018 influenza administration is shown. Data for influenza vaccines was obtained from the CDC’s FluVaxView. Comparative data is shown for the total vaccine administration volume in 2022 and projections for total vaccine administration volume in 2032, under an assumed forced seasonality and current vaccination behavior.
This would represent a formidable challenge when compared with the current immunization productivity in the U.S. During the 2022 to 2023 influenza vaccine season, 76% of the season’s total 173.37 million vaccines were administered during the peak season from September to December, according to the Center for Disease Control and Prevention’s (CDC’s) Flu VaxView 23 . In fact, according to the same database, approximately 85% of people 65 and older who were vaccinated by the end of the 2021–2022 season had received their influenza vaccine by the end of November 2021 23 . Averaging out the number of doses administered to that population over the number of days within an influenza vaccine season, this amounted to 1.1 million doses administered each day during that time period. Even with today’s vaccine volume of 200 million doses, assuming forced seasonality from September to the end of the year would result in a productivity of 1.9 million doses per day (13.1 million doses per week). That is significantly higher than the 0.4 million doses per day (3.1 million doses per week) administered during the COVID-19 vaccine’s peak season (Fig. 2B ). By 2032, assuming forced seasonality and current vaccination behavior, this could potentially escalate to 4.4 million doses per day (30.7 million doses per week). To cater to the projected annual volume of over 500 million vaccine doses by 2032, we would have to significantly augment this daily productivity rate, which would necessitate not just a change, but a necessitate a major paradigm-shift in our approach to vaccine administration and consumer vaccination behavior.
One solution could be to shift the administration window so that peak vaccination season begins earlier in the year. However, accommodating the growing number of vaccination options would require changes to our current approach. These changes could include expanding access to vaccination services, increasing public awareness and education, and implementing targeted interventions to drive behavior change. To-date, no comprehensive assessment has been conducted on what these changes might be or on stakeholder readiness, leaving many unprepared or even unaware of the evolving adult vaccine market. This presents a significant challenge, as without a clear understanding of the necessary changes and the readiness of stakeholders to implement them, it will be difficult to successfully execute this solution and achieve our productivity goals.
Breaking down barriers: a study on navigating the challenges of an evolving industry
To better understand the potential challenges and reactions to future states of the adult vaccine landscape, we undertook a market research study comprising both qualitative and quantitative approaches (see Supplementary Information for more study details; Supplementary Fig. 3 ). Our research methodology was built on an iterative, sequential primary market research design using mixed methods. This encompassed a five-step process that began with fact gathering and hypothesis identification. The initial fact-gathering stage involved an extensive exploration of existing knowledge, data, and available information on the potential evolution of the adult vaccine landscape. Based on this information, we developed hypotheses about potential future market state scenarios.
Qualitative interviews were conducted with key industry stakeholders (i.e., recommenders and funders, stocking and purchasing representatives, immunizers and advocacy groups, and consumers) from the U.S., with the aim of exploring their practices concerning the recommendation, funding, stocking, purchasing, immunizing, and advocacy for vaccines. The stakeholders were provided with the expected changes within the adult vaccine market (Supplementary Fig. 4 , Supplementary Fig. 5 , Supplementary Fig. 6 , and Supplementary Fig. 7 ). Two future scenarios were then presented to each stakeholder (Supplementary Fig. 8 ). The first scenario was optimistic, showing a future where stakeholders adapt and seize new opportunities, while the second scenario was pessimistic, illustrating a future where stakeholders maintain their usual practices that might not fit the evolving market. In this way, we sought to assess the stakeholders for their awareness of changes within the market and their perspectives on how these changes might be handled in the future.
We also conducted quantitative surveys among immunizers and adult consumers to measure the impact and compromises linked with alternative scenarios within the adult vaccine landscape. Our analyses aimed to characterize the degree of impact and trade-offs concerning U.S. future state scenarios.
While the totality of results from this study is too extensive for this perspective, we will center our focus on the crucial dynamics and issues that demand attention, ensuring stakeholders within the adult vaccine market are better informed as to how handle increasing demand without the system becoming overwhelmed and collapsing.
Ignorance, finger pointing, and overconfidence
Through interviewing and surveying key adult vaccine market stakeholders, we found that many stakeholders may not be fully cognizant of the impending wave of adult vaccines. The primary reason for this ignorance was the absence of incentives to assess situations beyond the current fiscal year, which fostered short-term thinking and hindered the identification of potential long-term effects within the adult vaccine market. This lack of awareness can also potentially lead to a lack of preparation and resulting missed opportunities as the stakeholders at the top of the value chain underestimate the challenge to adopt future adult schedules. Immunizers and consumers express more concern than other stakeholders regarding this impending change (Fig. 3 ), but there is a noticeable absence of proactivity. There is also currently no overriding policy body or cohesive national immunization plan in the U.S. to address these challenges.
Visual comparison of stakeholder preferences is provided across sensitivity scenarios. The sensitivity levels were determined using insights gained through the assessment of qualitative statements gathered from stakeholders (Recommenders & Funders, Stocking & Purchase, General Practitioners [GPs] & Primary Care Physicians [PCPs], Pharmacists, and Consumers). These quantitative statements were gathered in response to future market scenarios.
The adult vaccine market has also seen a shift in focus to newer participants, such as the rise of alternative vaccination sites like pharmacies, aiding a decades long trend which is expected to continue. Historically, adult vaccines have been distributed through various sources like primary care offices, pharmacies, and vaccine clinics 24 , 25 . However, primary care doctors tend to prioritize pediatric immunization 26 . Surprisingly, 66.3% of health care professionals (HCPs) in the U.S. do not check their patients’ vaccine statuses with every visit, and more than half (53.0%) do not even include vaccine administration within their practice scope 27 . This could limit immunization access for patients who rely solely on their primary care physician. In recent years, pharmacists have emerged as popular alternative vaccinators for adults, offering convenience with longer operating hours and proximity 28 , 29 , 30 , 31 .
However, this shift brings with it its own set of challenges. Most physicians recognize the benefits and convenience of pharmacists sharing the role of vaccinating adults; however, concerns exist about pharmacists’ access to patient medical records and vaccination history 32 . In fact, a degree of discord often exists between physicians and pharmacists, particularly concerning communication and collaboration within the office environment. While a synergistic relationship between these two parties can significantly enhance patient care, physicians are typically hesitant to grant pharmacists the authority to administer vaccines or offer advice concerning medications to ‘their patients’ 33 . On the other hand, pharmacists believe they possess the necessary skills to provide this support to patients, although they understand that many patients prefer receiving these recommendations directly from their physician.
Addressing these complexities requires fostering a sense of trust between pharmacists and physicians, which is paramount to the successful dissemination of future vaccines. It is crucial to nurture a “my pharmacist” mindset, where patients form a trusted bond with their pharmacist 33 . Regular interaction and cooperation between physicians and pharmacists are vital components of this success formula. Such collaboration allows the pharmacist to gain a comprehensive understanding of the patient’s medical history, thereby enabling them to identify any gaps in vaccination history. Furthermore, the establishment of a network comprising pharmacists collaborating closely with primary care physicians can bolster confidence in the pharmacists’ capability to administer vaccinations.
Another change brought on by the COVID-19 vaccine rollout is a feeling among many stakeholders, particularly GPs/PCPs and pharmacists, that they are prepared for the evolving adult vaccine landscape (Fig. 3 ). Some stakeholders during interviews drew parallels with the recent success of the COVID-19 vaccine distribution, expressing optimism that the expedited timelines witnessed during the pandemic can be replicated for future approved vaccines. This understanding underscores the confidence in our healthcare system’s resilience and adaptability, brought about by the unprecedented feats achieved during the pandemic. However, this view ignores the challenges faced during the COVID-19 vaccine rollout, which was initially slow and inefficient due to limited supply and logistical challenges 34 . The introduction of drive-through sites and mobile clinics increased access and speed 35 , but it is unlikely future vaccine rollouts will mirror this approach due to differences in urgency and resource allocation.
Stakeholders also anticipate that, in a non-pandemic environment, new offerings will be introduced gradually and cater to specific sub-populations (i.e., segmented recommendations), rather than blanket applications across the entire adult patient pool. However, it is crucial to remember that the post-COVID vaccine landscape is already witnessing the approval of new and innovative vaccines, such as vaccines for RSV, a trend which will likely continue over the next several years 36 . These products are expected to either target rare diseases, penetrate markets already served by existing vaccinations, and/or leverage the latest breakthroughs in vaccine technology. Such a dynamic environment calls for continued vigilance, flexibility, and a readiness to embrace change in our approach to vaccine administration and public health strategy.
Despite the expected increase in vaccine offerings, recommenders, funders, stockers/purchasers, and, to a lesser extent, immunizers anticipated limited challenges in adopting an expanded vaccine schedule. The lack of concern observed around the adoption of the expanded schedule likely mirrors a fragmented understanding among stakeholders. Each party tends to focus on its portion of the process, often overlooking the system’s holistic view and thereby underestimating the scale of change implicated. The adoption of expanding adult vaccines will be challenging in light of a lack of an existing cohesive national adult immunization schedule in the U.S. What currently exists is a category of approved products with recommendations governing their individual/disease area usage, which unfortunately may result in fragmented and inconsistent usage of adult vaccinations beyond what has already been established in the market (e.g., Influenza, Pneumo, Shingles).
Lack of market standardization
While there was little concern in adopting an expanded vaccine schedule, stakeholders in every category acknowledged the challenge in strategically prioritizing adult vaccines. However, no individual stakeholder group is willing to take responsibility for establishing priorities or developing schedules.
Currently, the task of assessing the potential influence of vaccines on public health and establishing vaccination guidelines falls to Vaccine Technical Committees (VTCs), such as the ACIP in the Centers for Disease Control and Prevention (CDC), and the National Vaccine Advisory Committee (NVAC). ACIP plays a pivotal role as the primary policymaker in adult immunization. It not only influences reimbursement decisions but also provides a product-specific adult immunization schedule that outlines the required doses or boosters, taking into account the patient’s age and risk factors 37 , 38 , 39 , 40 . The recommendations made by the ACIP are reviewed and usually adopted by the CDC director 41 . Once adopted, these recommendations become official CDC guidelines and are published in the Morbidity and Mortality Weekly Report (MMWR).
When a vaccine is not recommended for routine use, the ACIP will issue a SCDM recommendation. Unlike routine, catch-up, and risk-based recommendations, SCDM vaccinations are not recommended for everyone in a particular age group or everyone in an identifiable risk group. Rather, SCDM recommendations are individually based and informed by a decision process between the health care provider and the patient or parent/guardian 42 , a process that encourages informed and collaborative discussions that guide mutual decisions about the suitability of a particular vaccine 43 , such as the newly approved RSV vaccines that are recommended, using SCDM, for adults 60 years and older 44 . Although HCPs have mixed responses to SCDM recommendations, the majority support them for certain vaccines 45 . However, concerns persist about the additional time required for patient discussions, potential confusion, and the need for specific talking points to guide these conversations.
An integrated vaccine tracking system, like a national immunization information system (IIS), could significantly ease the intricacies associated with adult vaccination delivery 46 . An IIS can serve as a one-stop repository for immunization records, thereby streamlining the process of vaccination tracking and ensuring accurate records. Regrettably, the U.S. does not currently have such a unified national system in place. Instead, the responsibility falls on each individual state to devise its own protocols and systems. State policies can range from opt-in only (Texas) to mandatory (New York), and one state, New Hampshire, does not have an IIS 47 . Without a centralized national vaccination tracking system, patients find themselves coordinating with their HCPs to trace their vaccine history. This often leads to incomplete or inaccurate records due to miscommunication, gaps in data transfer, or simple human error 47 .
The lack of a national immunization plan and national IISs imposes a significant burden on immunizers, who are required to rapidly assess the disease risk level for each patient and determine which vaccines are most critical to recommend during that visit and which can be deferred to a later date. This confusion, in conjunction with perceived inadequate training, time constraints, and lack of emphasis on vaccinations, can hinder HCPs’ ability to effectively administer vaccines 27 , leading to suboptimal patient health outcomes.
Despite the challenges brought about by lack of market standardization in the adult vaccine market, there is little momentum for change. Unlike the pediatric market, the adult vaccine market has not had the necessity to standardize, and it lacks the uniformity of the pediatric market that allowed for streamlined standardization of recommendations and schedules. Adult populations also have more choice as to whether they receive immunizations, with many younger adults believing that there is no real need to vaccinate until they are older.
Unfortunately, our research revealed that it is not clear which stakeholder group would drive an effort for standardization, and there is no clear distinction as to who would make recommendations for new adult vaccines and based on what factors. This is a critical gap as trade-offs for new vaccines must be assessed between different disease risk profiles and budgets, with some vaccines slated to receive funding while others will not.
Estimating vaccine administration limits—‘The Battle of the Arm’
To quantify how patients and immunizers will navigate the increasing number of vaccine options, we assessed their perceptions on current and future vaccination habits. Specifically, we wanted to understand how many vaccines adults were willing to receive in a year and in a single appointment, and then compare that with the number of vaccination visits they intend to make each year.
Patients across all age and risk groups, when surveyed, reported their willingness to receive up to four vaccines per year, a perception that aligns with that of the immunizers (Fig. 4A ). Immunizers also appeared to overestimate the maximum number of vaccinations a patient would be willing to receive in a single appointment (Fig. 4B ). When asked, all patient groups responded that they prefer to limit the number of shots to two per visit, one for each arm. This would necessitate multiple appointments throughout the year to reach the 4 immunizations patients are willing to receive each year. However, all stakeholders appear to overestimate the maximum number of yearly vaccination visits a patient is likely to make, with patients and immunizers estimating at least two appointments annually (Fig. 4B ). This contradicts data from 2018 demonstrating that, on average, patients across all age groups made less than one preventative care appointment per year with their physician.
A quantitative online survey conducted in the U.S. was used to derive consumer ( n = 500) and immunizer ( n = 103) perceptions regarding a crowded vaccine schedule. A Consumer and immunizer reports for the maximum number of vaccines patients are willing to receive yearly. Consumers were asked “what is the maximum number of different vaccines you would be willing to receive in a year (some possibly requiring several appointments)?” Immunizers were asked “what is the maximum number of vaccines you expect an individual adult patient would be willing to receive in a year?” Results presented are for a “typical” patient with regard to vaccine attitudes, or one who is “busy” (e.g., working full-time). B Immunizer reports for the maximum number of vaccines they would administer in a single appointment, and consumer reports for the maximum number of vaccines patients are willing to receive in a single appointment. Consumers were asked “what is the maximum number of vaccines (individual shots) you would be willing to receive in a single appointment?” Immunizers were asked “What is the maximum number of vaccines (individual shots) you would be willing to give a typical patient in a single appointment? Please assume co-administration is supported by relevant data.” C The reported number of vaccination appointments patients schedule as reported by patients and immunizers compared to actual visits indicated by red lines. Consumers were asked “What is the maximum number of visits for a vaccination you would be willing to attend per year?” Immunizers were asked “How many visits per year for the purposes of getting a vaccine do you think patients would be willing to attend per year (on average)?” Results presented are for a “typical” patient. 2018 data was obtained from the CDC NCHS Data Brief No. 408, May 2021. Consumer data was collected for healthy/low-risk 18–64-year-olds. This data is used for both groups - healthy/low-risk 18–49-year-olds and healthy/low-risk 50–64-year-olds. Consumer data was not collected for pregnant women. D Consumer attitudes within future vaccination schedules. Consumers were asked “Thinking about this future with many different vaccine options available for adults like you, to what extent do you agree with the following statements?”.
Consumers were also presented with the future vaccine schedule to gauge their willingness to adhere to future recommendations (Fig. 4D ). Consumers (33%) still indicated a willingness to receive multiple vaccines per visit; however, 28% stated a strong preference to schedule more vaccination appointments rather than have more than 1 vaccine per visit. When asked if they would be able to attend more than one vaccination appointment per year in order to receive all recommended vaccines, 51% of patients strongly agreed. However, if the vaccination behavior observed in 2018 continues over the next decade, patients will need to be willing to receive vaccines at ‘non-wellness’ visits in order to receive the recommended number of vaccines.
The number of vaccination opportunities, however, is on the decline and the timeline within which to administer vaccines may become compressed. COVID-19 has increased the prevalence of telemedicine—acquiring medical care digitally - which may reduce face-to-face encounters between consumers and HCPs 48 . HCPs also must contend with forced seasonality, where nonseasonal vaccines are aligned or coadministered with flu vaccines. At this time, limited vaccination opportunities and forced seasonality do not represent significant barriers to immunization due to the manageable number of currently available vaccine products. Most of these products are also not seasonal and have primary series that do not have to be administered annually. However, as the number of vaccine products, particularly seasonal vaccine products, increase over the next couple of decades, HCPs will be faced with more immunizations, but still only one shot per arm per patient. This limited arm space will force the adult vaccine market to become embroiled in the ‘battle of the arm.’
To date, the limited variety of adult vaccines—just seven recommended by the CDC—has made managing vaccination schedules relatively straightforward (Supplementary Fig. 2 ). This has fostered a ‘there’s always next year’ attitude among patients. However, the increasing number of vaccines threatens to disrupt this status quo. Currently, adults aged 50 and 65 years old could be advised to receive a maximum of 2.8 and 3.5 of recommended vaccines, respectively, in a single visit depending on risk factors. These estimates were based on 50- or 65-year-old Americans (assuming average lifespan) who require all adult vaccinations, and who only received vaccines at annual appointments. In 10 years, we estimate that the number of recommended doses for adults aged 50 and 65 years is expected to increase to 5.6 and 6.4 per year, respectively.
The expansion of the adult vaccine market means that consumers will need to take more ownership of their vaccination schedules and records. Current vaccination policies are often developed around the assumption that consumer stakeholders will make rational decisions towards the betterment of their own health. However, behavioral economics and choice theory suggest that humans deviate from rational behavior in predictable patterns, especially when faced with an overwhelming number of options—a phenomenon known as choice paralysis. Unfortunately, our study revealed that an estimated 38% of patients already feel overwhelmed at the prospect of an increased volume of adult vaccines.
The COM-B (capability, opportunity, and motivation - behavior) model of behavior change, which suggests that vaccine uptake relies on capability, opportunity, and motivation, offers insights into strategies to overcome consumer choice paralysis and increase vaccine uptake 49 . As the number of available vaccines increases, HCPs will play a crucial role in helping patients navigate this changing landscape, making complex decisions about the prioritization and administration of vaccines. A physician’s recommendation, which has been proven to increase immunization rates 50 , can increase consumer’s knowledge (a form of capability) of available vaccines and provide persuasion (motivation) through the trust they have built with their patients. However, due to the limitations discussed above, physicians and other vaccine administrators may not have the capability, opportunity, or motivation to recommend immunizations to their patients. When interviewed, HCP respondents reported that they rely on morbidity and mortality weekly report (MMWR) recommendations to guide their vaccination choices and have no policy or training (planned or completed) to guide prioritization decisions and will vaccinate on patient preference. When shown the stimuli for the expected number of adult vaccines (Supplementary Fig. 4 ), they expressed a need for overarching recommendations on vaccine priority to be issued by the ACIP but doubt this will happen due to the complexities of adult care.
Delivering more vaccines via pharmacies and other non-traditional venues is one proposed solution for administering an increasing number of vaccines, though it calls for the creation of advanced data systems to ensure meticulous tracking of each patient’s vaccinations. Combination vaccines, which combine multiple vaccines into a single dose, could also help reduce the burden of prioritization and increase vaccine uptake. Though only one such vaccine currently exists for adults (Tdap for tetanus, diphtheria, and pertussis), more are anticipated in the future, including an influenza + COVID combination as well as a possible influenza + RSV combination.
The success of these solutions, however, hinges on patient acceptance. With vaccine hesitancy on the rise, patient acceptance is expected to be a major barrier to adult vaccination. In fact, the WHO has recognized vaccine hesitancy as one of the top ten global health threats 51 , and patient skepticism of new vaccines will likely increase if they are designed with new vaccine platforms and/or combinations. Therefore, education campaigns with trusted public health figures and community leaders will be key to improving patient acceptance of these vaccines. We must also look towards addressing the ‘Opportunity’ aspect of the COM-B model, as inequity in the adult vaccine landscape may limit access of new vaccines among disadvantaged demographics.
Lack of incentives and accountability—equity falling through cracks
Despite the fact that attaining optimal health requires an acknowledgement of and targeted efforts to address social or societal conditions contributing to health disparities, far too many in the U.S. still suffer from unequal access to healthcare 52 . Nearly four in ten lower-income adults have reported delaying medical care due to cost 53 . Such disparities have caused a divide in actual health outcomes, with lower socioeconomic status leading to a shorter life expectancy 54 . Bridging the equity gap, however, is not just a moral imperative but also a financial one. In fact, estimates suggest that by eliminating these racial disparities alone, we could save over $90 billion annually in unnecessary medical expenses 55 .
The U.S.’ vaccination landscape has long been affected by existing health disparities, with lower rates of coverage among certain racial and socioeconomic groups. This has been historically true for influenza and pneumococcal vaccinations, particularly for vaccinations with newer technologies 56 . One study found that only approximately 13% of black influenza vaccine recipients received the newer high-dose inactivated trivalent influenza vaccine, compared to approximately 27% of white recipients 56 . The COVID-19 pandemic only exacerbated this gap, as attitude towards the vaccine further decreased uptake of the influenza vaccination 57 . Furthermore, data has revealed disparities in COVID-19 vaccination rates among various demographics such as race, ethnicity, household income, urbanicity, political affiliation, and others 58 , 59 , 60 , 61 . These disparities exist despite unprecedented efforts to make vaccination available, free of charge regardless of immigration or insurance status, and to make vaccination convenient 62 , 63 . Other interventions, such as the Affordable Care Act and Inflation Reduction Act have improved adult vaccine coverage for insured individuals 64 , 65 ; however, they do not sufficiently support uninsured individuals or cover vaccines not recommended by the ACIP. Without targeted intervention, the introduction of new adult vaccines may worsen health equity gaps in the future.
Unfortunately, our market research has highlighted that no stakeholder group is individually accountable for addressing vaccine equity. We found a significant gap in understanding and responsibility within the vaccine ecosystem, leading to a disconcerting reality: equity is falling through the cracks. Each stakeholder we engaged was primarily focused on their specific goals, often assuming that someone upstream was responsible for ensuring equitable access to vaccines. This mindset is heavily influenced by cognitive biases such as groupthink - a psychological phenomenon where individuals seek conformity in a group, often ignoring contrary information or viewpoints, and anchoring bias—the tendency to heavily rely on the first piece of information encountered (the “anchor”) when making decisions 66 , 67 . Such biases create an environment where critical aspects of vaccine distribution and access are overlooked.
The most striking finding was the widespread belief that the ACIP shouldered the responsibility for implementing measures to ensure equity. However, this belief represents a fundamental misunderstanding of the ACIP’s role as an advisory committee that is responsible for creating and maintaining recommendations which consider a spectrum of equity measures, such as equitable inclusion in trials 68 . When interviewed, ex-ACIP members stated that they had no ability or remit to enforce activities beyond making recommendations.
This misplaced trust reverberates throughout the system, creating a perpetuating cycle where stakeholders’ focus on narrow objectives leaves broader equity issues unaddressed. The result is a systemic failure where lives are impacted or even lost due to diseases that could have been prevented with vaccination. For example, influenza hospitalization rates in the U.S. were nearly 80% higher among Black adults than White adults from 2009 to 2022 69 .
At the heart of this issue is the absence of systems thinking, or a holistic approach that takes into account structures, patterns of interaction, events, and organizational dynamics 70 . Stakeholders need to comprehend the interconnectedness and interdependencies within the vaccine ecosystem. Ensuring equity in vaccine access is a collective responsibility that requires the active involvement of all stakeholders, rather than being the sole obligation of a single entity.
Social cognition—a person’s ability to understand and function in the social world—plays a significant role in this context 71 . Cultural cognition, a subset of social cognition, influences how individuals perceive information and make decisions based on their cultural affiliations and identities 72 . For instance, a community’s collective understanding about vaccines can create a powerful social norm, influencing individuals’ attitudes and behaviors towards vaccination.
Behavioral economics provides valuable insights into these dynamics and how they can be addressed. For example, interventions that emphasize the social norm of vaccine acceptance can counteract the effects of groupthink by challenging the group’s consensus 71 . Likewise, understanding anchoring bias can guide the design of communication strategies. By ensuring the first piece of information individuals receive about vaccines is accurate and positive, healthcare providers can set a positive anchor that shapes subsequent perceptions 67 . However, these insights also highlight why many interventions to combat inequity achieve only limited or short-term success. They often fail to address the root causes of these biases and the systemic factors that contribute to them.
The most meaningful successes, such as the one seen at UT Southwestern, are comprehensive grassroots efforts that fill the void created by the current system 73 . These initiatives understand and address the local cultural cognition and social norms, leading to the effective promotion of vaccine acceptance within their target communities. However, the challenge of applying lessons learned from these grassroots initiatives lies in scaling these strategies nationally. Every community has its own cultural and social norms, meaning that interventions must be tailored and localized. Such efforts, which are often underfunded, require substantial community involvement and are highly resource-intensive, making them difficult, if not impossible, to scale.
While our analysis above has highlighted behavioral drivers that contribute to the issue of vaccine inequity, it is important to acknowledge that these factors are just one part of the larger systemic problem. Addressing behavioral drivers can help to mitigate some aspects of inequity, but it does not fully resolve the issue. In fact, a hyper-focus on factors behind vaccine hesitancy can often mask systemic issues, such as structural racism, that impact vaccine equity 74 . Even if we were successful in eliminating vaccine hesitancy, we would still face significant barriers in terms of access and affordability, particularly for lower-income and uninsured individuals 53 , 58 . This reality amplifies the need for a more comprehensive approach to vaccine equity beyond simply addressing vaccine hesitancy.
Moreover, the current reliance on downstream interventions, such as improving public awareness and promoting vaccine acceptance, often overlooks the upstream, structural issues that contribute to health disparities. To truly advance vaccine equity, we must adopt a holistic, end-to-end approach that transcends sectors and addresses all dimensions of the issue, including policy guidance, access, affordability, and social determinants of health. This includes forming multisectoral partnerships, focusing resources on the most vulnerable populations, and designing interventions that consider local dynamics. We need to prioritize equity in our monitoring and evaluation efforts, measuring not just outcomes but also impact. Only by doing so can we hope to ensure that equity does not fall through the cracks but forms the cornerstone of our healthcare system.
The adult vaccine market stands on the threshold of significant growth in the forthcoming years. Preparing to incorporate more vaccines into the existing ecosystem could lead to enhanced health and economic outcomes in the future. The time is ripe for proactive solutions that consider the pivotal role of the consumer and their choices, along with improved coordination and accessibility in a currently fragmented landscape. Such measures encompass the elimination of barriers to vaccine access, streamlining processes for reimbursement and operations, enhancing record-keeping, and equipping immunizers and patients with the necessary tools to instill confidence in current and future vaccines. It is crucial to overcome these equity barriers before the surge in vaccine products leads to wider disparities. Innovation across policymakers, payers, and healthcare systems, including centralized digital records and policy driven by behavioral economics, will propel these solutions forward. As a result, adult vaccination coverage could mirror the successes seen within the pediatric vaccine ecosystem, ultimately positioning adult vaccination as a formidable shield against numerous life-threatening diseases.
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We thank Andrew Hill and Marie Beitelshees (Bulmore Consulting, Lockport, NY, USA) for their editorial support and review in preparing this article. This work was funded by Pfizer.
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Jones, C.H., Jenkins, M.P., Adam Williams, B. et al. Exploring the future adult vaccine landscape—crowded schedules and new dynamics. npj Vaccines 9 , 27 (2024). https://doi.org/10.1038/s41541-024-00809-z
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Vaccine epidemiology: A review
1 (Formerly at) Department of Community Medicine, Gajara Raja Medical College, Gwalior, Madhya Pradesh, India
This review article outlines the key concepts in vaccine epidemiology, such as basic reproductive numbers, force of infection, vaccine efficacy and effectiveness, vaccine failure, herd immunity, herd effect, epidemiological shift, disease modeling, and describes the application of this knowledge both at program levels and in the practice by family physicians, epidemiologists, and pediatricians. A case has been made for increased knowledge and understanding of vaccine epidemiology among key stakeholders including policy makers, immunization program managers, public health experts, pediatricians, family physicians, and other experts/individuals involved in immunization service delivery. It has been argued that knowledge of vaccine epidemiology which is likely to benefit the society through contributions to the informed decision-making and improving vaccination coverage in the low and middle income countries (LMICs). The article ends with suggestions for the provision of systematic training and learning platforms in vaccine epidemiology to save millions of preventable deaths and improve health outcomes through life-course.
The benefits of vaccination, one of the most cost-effective public health interventions, have not fully reached target beneficiaries in many low- and middle-income countries (LMICs).[ 1 ] Though the field of vaccine research and vaccinology has received a lot of attention since the discovery of the smallpox vaccine by Edward Jenner (1749-1823) in 1798, more than two centuries later, an estimated 20% of deaths among children aged less than 5 years occur due to diseases preventable by currently licensed vaccines.[ 2 , 3 ] Since the discovery of smallpox vaccine, a number of vaccines have become available. “Vaccine research and vaccinology” had witnessed a sort of ‘renaissances in vaccine research and uses’ in the early 1970s and 1980s, and now in the 21 st century there are licensed vaccines against nearly 27 agents and ongoing research on candidate vaccines against nearly 130 agents.[ 1 ]
There is increasing recognition of the role of vaccines as proven lifesaving interventions and that of the epidemiological principles in maximizing the benefits of vaccines and vaccination. While vaccinology delves into understanding how vaccines work, epidemiology helps to ascertain whether a particular vaccine is needed in targeted population (or age group) or not? For physicians and vaccine users alike, epidemiology and immunology are two important fields in medical science and public health, which helps in the better appreciation of the promise and potential of vaccines. While immunology is essential for understanding vaccine-host interactions, epidemiology is essential for understanding the implications of a vaccination program on the community and individuals. “Vaccine epidemiology” could be described as an interface between public health, basic medical sciences, and clinical medicine aimed at maximizing the benefit of existing knowledge in these areas.
The learning and study of vaccine epidemiology could help in the following: To make decisions on how to choose vaccines for inclusion in a public health program; to assess the disease burden; to identify target pathogens for vaccine research; to identify sources and transmission pathways of disease-causing agents; to determine vaccination strategies; to design disease-specific control, elimination, and eradication strategies; to monitor performance indicators; to take steps to improve surveillance; and to measure the progress and impact of vaccination strategies.
This review article aims to outline the basic concepts and key principles of vaccine epidemiology, and to briefly describe how vaccination program managers and vaccinologists could use this knowledge and understanding in their respective fields of work.
The terms “vaccine” and “vaccinology” came into use soon after Edward Jenner discovered the smallpox vaccine. Jenner called the smallpox vaccine “variola vaccinae.” For his contribution, Jenner is often referred to as the “Father of Vaccinology” (though this epithet is sometimes also used for Louis Pasteur). The word “vaccine” originated from vacca , a Latin term for the cow.[ 4 ] The credit for the first use of the term “vaccine” goes to Swiss physician Louis Odier (1748-1817), and the terms “vaccination” and “to vaccinate” were first used by Richard Dunning (1710- 1797).[ 5 ]
Epidemiology, which literally means “the study of what is upon the people,” is derived from the Greek epi meaning “upon, among,” demos meaning “people,” and logos meaning “study or discourse.” Physicians from the times of Hippocrates (460-370 BC) tried to understand the pattern of diseases in the community, though the term “epidemiology” was first used to describe the study of epidemics in 1802 by the Spanish physician Villalba in the Epidemiología Española .[ 6 ] In modern times, John Snow (1813-1858) and William Farr (1807-1883) pioneered the work on epidemiology and are often referred as one of the “fathers of modern epidemiology.”[ 7 , 8 ] Epidemiology, though practiced from earlier times than vaccinology, gained attention and prominence in the 19 th century. Now, the practice of vaccinology has become closely linked with that of epidemiology.
Key Concepts in Vaccinology
A vaccine is “an inactivated or attenuated pathogen or a component of a pathogen (nucleic acid, protein) that when administered to the host, stimulates a protective response of the cells in the immune system,” or it is “an immune-biological substance designed to produce specific protection against a given disease.”[ 9 ] The process of administering the vaccine is called vaccination. In other words, vaccination is the process of protecting susceptible individuals from diseases by the administration of a living or modified agent (e.g., oral polio vaccine), a suspension of killed organisms (as in pertussis), or an inactivated toxin (as in tetanus). Immunization is “the artificial induction of active immunity by introducing into a susceptible host the specific antigen of a pathogenic organism.”[ 9 ] However, immunization and vaccination are often used interchangeably. Vaccinology combines the principles of microbiology, immunology, epidemiology, public health, and pharmacy, amongst other.
The aim of vaccination is to protect individuals who are at risk of a disease. The children, the elderly, immune-compromised individuals, people living with chronic diseases, and people living in disease-endemic areas are those most commonly at risk. Vaccination is a common strategy to control, eliminate, eradicate, or contain disease (i.e., mass immunization strategy). If one wishes to learn about and understand vaccines, vaccination, and immunization programs, one needs to start with the understanding of key terms such as “antigen,” “antibody,” “immunoglobulins,” and “antisera,” among others. These are often described in the textbooks on this topic and therefore not covered in this article.
A vaccine is different from immunoglobulin in that the vaccines help in developing protective antibodies in the body of the individual to whom these are administered, and protection is available after a lag period of a few weeks to several months. However, immunoglobulin provides immediate protection. The vaccine administration is followed by two types of immune responses: Primary and secondary [ Figure 1 ].[ 9 , 10 ]
Primary and secondary response
Note: The primary series is the vaccine dose required for a primary response. There is a slow development of antibody in the body after the first dose of the vaccine is administered, and it usually takes 3-4 weeks to reach the peak antibody response. When a subsequent dose is administered (booster dose), a higher and quicker immune response is received (secondary immune response)
There are different types of vaccines: Live, killed, conjugate, component, and recombinant vaccines. While live vaccines provide protection after the administration of a single dose (though not always), the nonlive (or killed) vaccines usually require multiple doses for a satisfactory primary response. A minimum of 4 weeks’ interval is required between successive doses, though a longer interval (often, 8 weeks is considered optimal) results in higher antibody levels. The booster doses are generally given 6 or more months after the completion of the primary series. The booster doses have rapid and higher antibody response, a higher affinity for antibody production, and provide longer duration of protection (this is linked to secondary immune response).[ 11 ]
The antibody responses to vaccines are usually identified by “the correlates of protection,” an immune response that is responsible for and statistically interrelated with protection and usually linked to B-cell dependent response. Though, for a number of new vaccines, it is assumed that T-cells also play a role in correlates of protection. The correlates of protection are identified by animal challenge models and efficacy trials.[ 12 ]
Key Concepts in Epidemiology
Epidemiology pinpoints the weak links in the chains, sources, and transmission pathways of the pathogen so that the interventions can be directed. The understanding of epidemiology is required from the very early stage of priority-setting for disease burden, understanding the basis of correlates of protection, development of vaccines, evaluating different vaccination strategies including epidemiological and economic modeling, deciding national vaccination strategies, developing surveillance mechanisms, impact assessment, and designing vaccine introduction strategies.
The term “disease burden” or burden of disease (BoD) occupies a key place in epidemiology. The BoD could be measured by incidence or prevalence of a disease (prevaccine and postvaccine); severity/mortality (measured as case fatality ratio, hospitalization, and disease sequelae); disability [measured by disability-adjusted life years (DALYs)] and quality-adjusted life years (QALYs)]; economics (measured by cost-effectiveness, cost benefit, and cost utility); and social aspects (measured by societal disruption, economic disruption, and household impact).[ 13 ] The key concepts and study designs (i.e., cross-sectional, case-control, nested case-control, cohort studies) to understand epidemiology (disease occurrence and trends) are well, documented and thus not described in this article.[ 14 , 15 , 16 ]
However, vaccine probe studies requires special mention here, a vaccine probe study is a randomized cluster trial of a vaccine in which, usually, vaccine effectiveness (in other trials, usually efficacy is assessed) endpoints are used. The difference in the incidence of disease between vaccinated and unvaccinated children represents the vaccine-preventable disease burden. These are technically vaccine-effectiveness trials and have been used to measure the vaccine-preventable proportion/incidence of clinically (not microbiologically) defined outcomes. This approach has been used successfully in several countries for studies on Haemophilus influenzae type b (Hib) conjugate and pneumococcal conjugate vaccines.[ 17 , 18 ]
Vaccine epidemiology is the study of the interactions and effects of vaccines (and vaccination programs) on epidemiology of vaccine preventable diseases. Understanding the pattern of disease by geographical, rural-urban, and gender variations, linkage between disease burden and immunization coverage is based on principles of epidemiology. Which time of the year the polio mass immunization campaign should be conducted? For conducting mass campaigns, which age group should be targeted? Where should immunization efforts be concerted? Why do outbreaks occur? Why is it that some children do not suffer disease even though they have not received any vaccination? These are some of the questions answered through the application.
Basic reproductive number (R o )
Basic reproductive number or R o , measures “the average number of secondary cases generated by one primary case in a susceptible population.”[ 19 ] A number of factors determine its magnitude, including the course of infection in the patient and the factors that determine transmission between people. The magnitude of R o varies according to location and population. It is strongly influenced by birth rate, population density, and behavioral factors.[ 19 ] The magnitude of R o can be ascertained by cross-sectional and longitudinal serological surveys.
For organisms to survive:
- R o = 1 (A primary case must attempt to generate at least one new case)
- R o > 1 (Expansion of infected individuals)
- R o < 1 (Shrinking pool of infected individuals).
To calculate the magnitude of R o , a few key epidemiological, demographic, and vaccination program-related parameters should be known.[ 19 ] Parameters such as average age at infection prior to mass vaccination, life expectancy of the study population, and the average duration of protection by maternal antibodies should be considered. While the life expectancy and average age of protection by maternal antibody are known, the average age of infection prior to mass vaccination has been studied in select populations and is provided in Table 1 .[ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] A number of studies have been conducted in different parts of the world to assess the average age of infections and to derive the basic reproductive number.
Average age of infection and basic reproductive number of select diseases[ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]
This information could be used to estimate the fraction of each birth cohort that must be immunized to block transmission of a given disease. R o provides assessment of the critical fraction of each population immunized if eradication is targeted.
Force of infection
The “force or rate of infection” is “the risk of being infected.” The force of infection depends on the prevalence of infectious individuals, rate of contact between individuals, infectiousness of individuals, etc. As transmission is a dynamic process, force of transmission can change over a period of time.[ 28 ]
Vaccine efficacy and effectiveness
Vaccines have effect at both individual and population levels. The “biological or individual level effect” of vaccines includes effects on susceptibility (VE s ), on infectiousness (VE i ), and on disease progression (VE p ). The “population level effects” of vaccination depend on the coverage and distribution of the vaccines, as well as on how well different groups mix with each other.[ 29 , 30 , 31 ] These effects could result from the biologic as well as behavioral effects of the vaccination. Overall, the public health effect of vaccination programs depends on the effect in both vaccination and the unvaccinated population. This gives at least three types of population level effects of vaccination:
- Indirect effect : The population level effect of widespread vaccination on people not receiving vaccine
- Total effect : Combination of population level effect and effect of vaccination on individuals receiving vaccine
- Overall public health effect : The effect of vaccination program based upon weighted average of indirect effect on the individual not receiving vaccine and total effect on individual receiving vaccination.
In this context, the terms “vaccine efficacy,” “vaccine effectiveness,” and “program effectiveness” are commonly used. Vaccine efficacy is the percentage reduction in disease incidence attributable to vaccination (usually) calculated by means of the following equation:
VE (%) = (RU - RV)/RU × 100
where RU = the incidence risk or attack rate in unvaccinated people and RV = the incidence or attack rate in vaccinated people.[ 29 , 30 ]
The equation for vaccine efficacy can be reformulated as:
VE = 1 -RV/RU × 100
where RV/RU is the relative risk or rate ratio in vaccinated and unvaccinated people.
The vaccine efficacy is measured by observational studies under field conditions within a vaccination program or measured by trials conducted under normal program conditions. The vaccine efficacy for a number of vaccines is known, such as Measles 90-95%; mumps: 72-88%; and rubella 95-98%.[ 32 , 33 ] In vaccine trials, the vaccine's efficacy (among other things, including safety) is assessed. This is an important criterion for licensing of the vaccines and for making decisions on programmatic use. Vaccine efficacy is dependent on internal or individual factors, for example the efficacy of the measles vaccine depends on the presence of inhibitory maternal antibodies, the immunologic maturity of the vaccine recipient, and the dose and strain of the vaccine virus.[ 34 ]
Vaccine effectiveness is the sum of the reduction in the clinical events that might be expected to be associated with the disease.[ 28 , 29 ] Under program-based conditions, the effectiveness of the measles vaccine depends on the coverage, cold chain maintenance, correct injection techniques and safety, inaccurate recordkeeping/recall resulting in misclassification errors, and population-specific factors [human immunodeficiency virus (HIV) infection, malnutrition, etc.]. The most commonly used study design to assess a vaccine's effectiveness is a retrospective case-control analysis, and the odds ratio thus obtained can be used to calculate vaccine effectiveness, as follows:
Effectiveness = (1-OR) × 100
Vaccine effectiveness could be assessed by observational studies: Cohort studies, household contact study, case-control study and screening. How the information from screening could be used for estimating of vaccine efficacy is shown in Figure 2 .[ 35 , 36 ]
Relationship between percentage of cases vaccinated and vaccine efficacy
Note: With this figure, vaccine efficacy could be assessed by the following formula: PCV = [PPV- (PPV*VE)]/[1-(PPV*VE)]. Here, PCV = Proportion of cases occurring among vaccinated individuals, PPV = Proportion of population vaccinated, and VE = Vaccine efficacy. If any of the two values in this formula is known, the third value can be derived
Vaccine efficacy and effectiveness have often been used interchangeably in scientific literature. Vaccine effectiveness is often referred to as vaccine efficacy in field conditions. In other words, vaccine effectiveness is a combination of vaccine efficacy and field conditions such as coverage, immune status of population, and conditions under which the vaccine was administered (cold chain). In general, efficacy is higher than effectiveness. However, vaccines that show herd effect could have higher effectiveness than vaccine efficacy. For example, under program conditions, vaccine effectiveness is lower than vaccine efficacy, while herd effect improves effectiveness and can take it above efficacy. If analyzed from an outbreak, the formula for estimation of vaccine effectiveness is: Attack rate among vaccinated (ARV) vs attack rate among unvaccinated (URU). The formula used for assessing vaccine efficacy with this information is: Vaccine Efficacy (VE) = (ARU-ARV)/ARU*00.[ 35 , 36 ]
The “program effectiveness” refers to “the effectiveness of all antigens in an immunization program at implementation level at district, state and national levels.” The program effectiveness is also assessed by analyzing the trends in the occurrence of vaccine-preventable diseases (or VPDs) in identified settings and situation, before and after vaccine introductions. Overall mortality reduction is often considered as an indicator of vaccine program effectiveness/impact. Program effectiveness is the combination of more than one vaccine's effectiveness. Impact is the population level effect of a vaccination program, which depends on many factors, including vaccine efficacy, herd immunity, and effectiveness.
Study Designs to Assess Vaccine Efficacy and Program Effectiveness
Serological and epidemiological studies can be used to determine vaccine efficacy and program effectiveness with minor methodological adoptions.[ 9 , 15 , 16 , 18 , 33 , 34 , 35 , 36 ] Among serological studies, two sub types of studies are utilized for vaccine efficacy: Seroconversion studies and seroprevalence studies. Seroconversion studies are useful in measuring the induction of an immune response in the host. In the absence of disease, it indicates the persistence of antibodies and immunity. These studies are particularly useful in choosing the appropriate age for vaccination. Seroprevalence studies monitor the prevalence of antibodies due to disease in the population and indicate the pattern of occurrence of diseases.
The epidemiological approaches measure the ARV and ARU in various settings. Thereafter, the formula suggested above could be used for estimating vaccine efficacy. The epidemiological study designs[ 9 , 15 , 16 , 18 , 33 , 34 , 35 , 36 ] include:
- Double-blind, randomized, placebo-control trials: The ideal vaccine efficacy study is a clinical trial starting with persons susceptible to disease. However, such studies are not possible after the vaccine is licensed, as it becomes unethical to use placebo when the vaccine is of proven benefit
- Observational cohort studies: These are conducted when the randomized-controlled trials or secondary attack rate trials are not ethically justified, or are not feasible due to low incidence of the disease, or there is a requirement for long-term follow-up for the calculation of efficacy (e.g., hepatitis B vaccination in neonates, or where the number of individuals is too large to follow up)
- Case-control studies: These studies are most useful when personal immunization records are not generally available but some other sources such as records from clinics can be obtained. Case-control studies may be useful when prospective controlled trials are not feasible due to low incidence of disease
- Stepped wedge design studies: These are used when previous studies have indicated that the intervention is likely to be beneficial and the public health needs to introduce the intervention precludes withholding it from a population. The intervention is introduced in phases, group by group, until the entire target population is covered. The groups form the unit of randomization
- Outbreak investigations (Community-wide, total population, or population clusters): Such studies are best done when the outbreak is in a defined population, such as a village, town, city, or school
- Secondary attack rates in families and/or clusters: The assessment of secondary attack rate in family members of the “index case” provides a good opportunity to assess vaccine efficacy
PCV = [PPV- (PPV*VE)]/[1-(PPV*VE)]
where PCV = proportion of cases occurring among vaccinated individuals; PPV = proportion of population vaccinated; and VE = vaccine efficacy. If any of the two values in this formula is known, the third value can be derived [ Figure 2 ].
- Cluster Survey Method: In some of the endemic areas, vaccine efficacy can be assessed, even in the absence of an outbreak, by using coverage survey methods.
Other Important Concepts in Epidemiology
When a person who has been fully vaccinated develops the disease against which she/he has been vaccinated, it is referred to as vaccine failure. This could be of two types-
- Primary vaccine failure occurs when the recipient does not produce enough antibodies when first vaccinated. Infection can therefore occur at any time post vaccination. For example, this occurs in about 10% of those who receive the measles, mumps, and rubella (MMR) vaccine[ 37 ]
- Secondary vaccine failure occurs when adequate protective levels of antibodies are produced immediately after the vaccination, but the levels fall over time. The incidence of secondary vaccine failure therefore increases with time after the initial vaccination and hence booster doses are required. This is a characteristic of a number of the inactivated vaccines.[ 37 ]
Herd immunity and herd effect
Herd immunity may be defined as the resistance of a group or a community in total, against the invasion and spread of an infectious agent as a result of a large proportion of individuals in the group being immunized. Herd immunity or contact immunity develops in the case of certain live vaccines (e.g., OPV), wherein the nonvaccinated individuals also develop immunity to the pathogen just by coming in contact with the vaccinated individual.[ 38 ]
The level of herd immunity can be assessed through cross-sectional and longitudinal serological surveys. The serological surveys are usually based on serum or saliva in viral infections and activated T-cells for bacterial and protozoal infections. There are a number of quantitative assays, too.[ 39 ]
Additionally, immunological and disease surveillance methods provide the empirical base for the analysis and interpretation of herd immunity. Mathematical and statistical methods play an important role in the analysis of infectious disease transmission and control. They help to define both what needs to be measured, and how best to measure and define epidemiological quantities. The level of herd immunity can be measured by reference to the magnitude of reduction in the value of R o .[ 22 ]
Herd immunity threshold (H) is defined as the minimum proportion to be immunized in a population for elimination of infection.
H = 1 - 1/R o = (R o -1)/R o As the immunization coverage increases, the incidence and prevalence rates may decrease not only due to the direct effect of immunization per se but also because of indirect effects, such as the development of herd immunity and herd effect.[ 38 , 40 ]
“Herd effect” or “herd protection” is “the reduction of infection or disease in the unimmunised segment as a result of immunising a proportion of the population” or is “the change induced in epidemiology (incidence reduction) among unvaccinated members when a good proportion is vaccinated.” Herd effect is seen only for infections where humans are the source, and it extends beyond the age the vaccine is given, i.e., Haemophilus influenzae type B (Hib) vaccine is given to infants and protected other under-5 children, flu vaccine to children and beneficial effect among other family members.
Epidemiologic shift or transition
Epidemiological shift or transition denotes the change in the pattern of disease in a specified population. The impact on the person characteristics of a disease is the shift in the age of occurrence and severity of the diseases as observed consistently in communities with partial immunization coverage or immunization coverage for specific age groups only. A number of factors including the age at the time of vaccination, target population for vaccination, serotypes covered by the vaccines (where the disease in question is caused by multiple serotypes), and overall vaccination coverage may affect the epidemiological shift or transition.[ 41 , 42 ]
The phenomenon has importance in diseases such as hepatitis A, rubella, and varicella, wherein the severity of disease worsens with advancing age. It also has significance in diseases where multiple serotypes are associated with the diseases such as pneumococcal diseases and when targeting specific serotype by vaccine may lead to the emergence of other types of serotypes. The epidemiological shift or transition sometimes may offshoots the benefits accrued by the vaccination program. This showcases the need for tracking the epidemiological changes in the vaccination programs and initiating appropriate corrective measures.
One of the well-documented example of epidemiological shifts has been documented from Greece, following the introduction of MMR vaccine in public health program of the country. When the MMR vaccine was introduced in 1975 in Greece, the coverage with the vaccine was around 50-60% of the cohort, which reduced the incidence of diseases in the targeted population; however, shifted the average age of infection to older population. However, the susceptible cohort of un-vaccinated continued to increase over period of time with epidemiological shift to older age groups. By the early 1990s, specially those unvaccinated girls reached in the reproductive age group, still susceptible to rubella virus disease. In such cases, if the infections happened during the time of pregnancy, it led to development of congenital rubella syndrome (CRS) in fetus/infants. In 1993, it was noted that Greece had the highest incidence of congenital rubella syndrome (CRS).[ 42 ] This example highlights the need and importance for high coverage at the time of vaccine introduction and sustenance of the coverage in the subsequent cohorts. This situation is sometimes referred to as “perverse outcome,” where disease severity increases with age at infection: Vaccination can increase the burden of severe diseases, by raising the average age of infections. The total number of infections falls but the total number of severe disease increases, e.g., CRS, measles, encephalitis, and orchitis due to mumps.
Vaccine-preventable Disease Surveillance
Disease surveillance is another public health and epidemiology tool. A functioning disease surveillance system helps in understanding disease epidemiology before vaccines are introduced. Thereafter, it guides how well the vaccination program is doing in reducing the BoD. It helps in decisionmaking on the introduction of vaccines and also in assessing the impact of interventions. Unfortunately, the disease surveillance system in the majority of the LMICs requires a major boost.
The models are often referred to as “tools for thinking and simplification of systems,” suitable for analysis.[ 43 ]
Epidemiology aims to measure the disease burden; however, where measurement is not practical, estimates must be developed. The modern epidemiological methods and disease modeling have reached the level where accurate projection can be made based on existing knowledge and information. The estimates derived from various sources are often used in vaccination programs. The estimates are used for decisionmaking at local levels (i.e., state and national levels), for deriving estimates for neighboring countries (with similar settings) and for global (or international) levels. The estimates, if done with similar methods can provide useful information for interstate, intercountry, and interdisease comparisons, to observe the disease trend over a period of time, and for comparison of choices between intervention versus none versus others
In vaccination programs, a number of models are used:
- A static or decision analysis model is used on the assumption of a constant force of infection (or fixed risk). These models are more commonly used for noninfectious diseases. The static models are usually applied to a single cohort[ 45 ]
- Markov models[ 46 ]
- Dynamic model used for infectious diseases. Suspected, infected, and recovered (SIR) approach is an example of a dynamic model. These models are applied to multiple cohorts.[ 47 ]
Economic evaluation in healthcare addresses the question whether an intervention or procedure is worth doing when compared with other possible uses of the same resources.[ 44 ] This is based on the premise that resources are finite and there are opportunity costs. In such analysis, both costs (resources used) and outcomes (benefits) are considered. There are number of analyses including cost-effective analysis, cost-benefit analysis, cost analysis, and cost utility analysis.
Immunization Program Assessments and Evaluations
It is imperative to ensure the quality of immunization services is evaluated and assessed on a regular basis. The epidemiological methods provide useful tools for such evaluations.
- Thirty cluster survey: This is standard World Health Organization (WHO) methodology to determine immunization coverage based on a survey of small number of individuals (for example, 210 in 30 clusters of seven children each). The home visits are made and a immunization record or history is taken for children aged 12-23 months. The survey provides fairly correct information about immunization coverage in the area. However, it is important that these clusters are selected based on standardized methodology and statistical tools[ 48 ]
- Seventy-five-household survey: In this approach, 75 households near the health facility are surveyed. This methodology follows the notion that the households closest to the facilities can provide the best estimates of immunization coverage[ 49 ]
Missed-opportunity survey, Lot quality assurance survey (LQAS), the multiple indicator cluster survey (MICS), and coverage evaluation surveys (CES) are the other methods.[ 49 ]
Application of Vaccine Epidemiology in Vaccination Programs
Vaccine epidemiology, as described in the earlier sections, is a multidisciplinary science. It has a role to play from vaccine research (proof-of-concept stage and then in clinical trials), in decisionmaking on new vaccine introduction, and once vaccines are introduced in the post-marketing surveillance and other aspects. The practice of vaccinology is gathering momentum since the first immunization schedule was published by the WHO in 1961.[ 50 ] Now in the 21 st century, there are more licensed vaccines, more in the pipeline, more number of people than ever receive vaccines. There is an increasing amount of research in laboratories, deliberations in academic institutions, and policy discourses in ministries of health about vaccines and vaccination schedules. There is an increasing awareness within the general public about vaccines and vaccination schedules.
One of the important development in the last 2 decades has been that the electronic media and the Internet have empowered people with information. The information received from various sources on the Internet is mostly useful for parents and the general public but is not always correct. At times, it reflects one sided view, and people with vested interests may misuse the information and media. The risk of such incomplete information has been reflected in some of the recent outbreaks of measles in European countries where the Internet has been a major source of information, and people used this source for decisionmaking. Such misinformation has affected the adoption of human papillomavirus (HPV) vaccination in a few countries.[ 51 , 52 ] These examples reflect the two sides of technology, which can help in increasing coverage of vaccines but could also spread misinformation which can lead to disease outbreaks.
The incidences of “vaccine refusal” or “vaccine hesitancy” are increasing.[ 53 ] This is an area in which the knowledge and understanding of vaccine epidemiology could help in improving immunization coverage (or at least prevent undesired fall in immunization coverage). The vaccine epidemiology can help in responding to the misinformation and addressing the challenge. Vaccine epidemiology can provide guidance in understanding which diseases are common in which parts of the world and therefore help in decisionmaking about which vaccine should be received by the people traveling to particular endemic countries. It guides in the selection of vaccines for special target groups, i.e., pregnant women, the elderly, and in the changing context.
The disease surveillance system is often used to measure the impact of vaccination programs on disease burden. The vaccine preventable diseases surveillances system could provide useful insight on the benefits of vaccination and is an important tool for programmatic modifications and advocacy. The National Immunization Technical Advisory Groups (NITAGs) use vaccine epidemiology for decision making. The national vaccination policies and immunization guidelines need to be informed by the vaccine epidemiology.
There are important roles of vaccine epidemiology in reducing morbidity and mortality from vaccine-preventable diseases. This knowledge could be best utilized by policy makers for immunization program decisionmaking and by family physicians and public health specialists for advising individuals on the benefits of vaccination.
In LMICs there is limited capacity for training in vaccinology and epidemiology. There are very few training opportunities and courses that teach vaccine epidemiology. It is a paradox that countries requiring maximum capacity have very limited opportunity. This affects both vaccine research and decisionmaking.
In the absence of sufficient capacity, the country program managers in LMICs often have to rely on international experts for decisionmaking. This adversely affects the reputation and credibility of the country's program managers and raises questions regarding the decisionmaking process, contributing to the delay in the benefits of proven interventions reaching those who are most susceptible to vaccine-preventable diseases.
The understanding of vaccine epidemiology has potential to save additional lives from vaccine preventable diseases and improve health outcomes through life course. The vaccine epidemiology has definitive role in extending the benefits of vaccines to additional populations and in the selection of target groups for vaccination, amongst other. However, systematic efforts would be needed to translate this knowledge into actions. The mechanisms and institutional capacity has to be built into low and middle income countries (LMICs) on vaccine epidemiology. The national governments and international development partners need to support and promote courses and training programs for vaccine epidemiology, and the academic communities need to work together. Vaccine epidemiology should be part of key modules in the teaching of undergraduate and postgraduate medical students. Public-health program managers and policy makers should be trained in vaccine epidemiology through continued medical education and on-the-job training programs.
The opinions expressed in this article are solely those of the author and should not be attributed to any institution/organization he has been affiliated to in the past or at present.
The author has immensely benefitted from the interactions with many eminent vaccine experts, epidemiologists, academicians, and public-health program managers. A few of the concepts presented in this article could have been (knowingly and unknowingly) borrowed, developed, and influenced by the author's interactions with national and international experts in these areas. I would like to acknowledge their teaching and influence. Special thanks are due to Dr. Dewesh Kumar, All India Institute of Medical Sciences, Jodhpur, Rajasthan for support in literature review.
Source of Support: Nil.
Conflict of Interest: None declared.
COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign
- 1 Biology and Nutritional Epidemiology, Independent Research, Copper Hill, USA.
- 2 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, USA.
- 3 Biostatistics and Epidemiology, Independent Research, Research Triangle Park, USA.
- 4 Immunology and Public Health Research, Independent Research, Ottawa, CAN.
- 5 Epidemiology and Biostatistics, Independent Research, Basel, CHE.
- 6 Data Science, Independent Research, Los Angeles, USA.
- 7 Cardiology, Epidemiology, and Public Health, McCullough Foundation, Dallas, USA.
- 8 Cardiology, Epidemiology, and Public Health, Truth for Health Foundation, Tucson, USA.
- PMID: 38274635
- PMCID: PMC10810638
- DOI: 10.7759/cureus.52876
Our understanding of COVID-19 vaccinations and their impact on health and mortality has evolved substantially since the first vaccine rollouts. Published reports from the original randomized phase 3 trials concluded that the COVID-19 mRNA vaccines could greatly reduce COVID-19 symptoms. In the interim, problems with the methods, execution, and reporting of these pivotal trials have emerged. Re-analysis of the Pfizer trial data identified statistically significant increases in serious adverse events (SAEs) in the vaccine group. Numerous SAEs were identified following the Emergency Use Authorization (EUA), including death, cancer, cardiac events, and various autoimmune, hematological, reproductive, and neurological disorders. Furthermore, these products never underwent adequate safety and toxicological testing in accordance with previously established scientific standards. Among the other major topics addressed in this narrative review are the published analyses of serious harms to humans, quality control issues and process-related impurities, mechanisms underlying adverse events (AEs), the immunologic basis for vaccine inefficacy, and concerning mortality trends based on the registrational trial data. The risk-benefit imbalance substantiated by the evidence to date contraindicates further booster injections and suggests that, at a minimum, the mRNA injections should be removed from the childhood immunization program until proper safety and toxicological studies are conducted. Federal agency approval of the COVID-19 mRNA vaccines on a blanket-coverage population-wide basis had no support from an honest assessment of all relevant registrational data and commensurate consideration of risks versus benefits. Given the extensive, well-documented SAEs and unacceptably high harm-to-reward ratio, we urge governments to endorse a global moratorium on the modified mRNA products until all relevant questions pertaining to causality, residual DNA, and aberrant protein production are answered.
Keywords: autoimmune; cardiovascular; covid-19 mrna vaccines; gene therapy products; immunity; mortality; registrational trials; risk-benefit assessment; sars-cov-2 (severe acute respiratory syndrome coronavirus -2); serious adverse events.
Copyright © 2024, Mead et al.