Restoring Trust: The Need for Precision Medicine in Infectious Diseases, Public Health and Vaccines

ABSTRACT

There are limited data on precision medicine in infectious diseases and vaccines; however, precise management of infectious diseases plays a critical role in trust for government, health-care organizations, science, and pharma. The improvement in biomedical technologies, availability of large clinical and -omic data and appropriate application of artificial intelligence may allow precision in vaccines and public health and restore trust. This is an invited editorial on the role of precision medicine in infectious diseases and vaccines.

Introduction

Precision medicine is often simply described as “personalized medicine” and it is defined by the U.S. Food and Drug Administration (FDA) as “an innovative approach to tailoring disease prevention and treatment that takes into account differences in people’s genes, environments, and lifestyles.”¹ The goal of precision medicine is to provide the most effective and safest health-care intervention to a patient.¹

Most of the literature on precision medicine is in oncology. There is limited literature on precision medicine in the fields of infectious diseases and vaccines. A PubMed search conducted on February 19, 2023, showed that since 1952, 94770 precision medicine papers were published. Among them, 37369 (39%) are indexed with the keyword “cancer,” 3,485 (4%) are indexed with the keyword “infectious diseases” and 436 (0.5%) are indexed with the keywords “infectious diseases and vaccine.” Interestingly, the majority of precision medicine infectious diseases papers were published after 2020 (Figure 1).

Figure 1.

Bar graph showing results of a PubMed search for papers published on precision medicine in the field of infectious diseases and vaccines for the years 2020, 2021, 2022 and 2022 conducted on February 19^th, 2023.

Why is precision in infectious diseases necessary?

Infections are among the top 10 global public health concerns.² The World Health Organization (WHO) reports that infectious diseases are responsible for the deaths of over 17 million people annually.² Compared to other diseases, infections affect the largest number of people, may emerge over weeks and months, quickly expand beyond the original geographical boundaries, and can cause serious morbidity and mortality as well as economic damage globally.^3,4

For example, almost everyone is infected with cytomegalovirus (CMV) as a child; according to a recent study, the global seroprevalence of CMV IgG was 83.16% (95% confidence interval [CI]: 78.55–87.77%, I2 = 99.5%).⁵ CMV may reactivate during times of immune suppression later in life and cause disease. The majority of children also experience respiratory syncytial virus (RSV) infection before two-years-of-age.⁶ In addition, according to the Global Tuberculosis Report, in 2019 approximately 10 million people developed tuberculosis (TB) disease.⁷ The number of deaths due to TB was approximately 1.4 million and was similar to the number of deaths due to respiratory tract cancers (IHME Global Burden of Disease 2019).⁷ Most recently, the COVID-19 pandemic spread at an alarming rate, affecting every country in the world within 12 months.⁸ Before the emergence of the COVID-19 pandemic, Influenza was the prototypical pandemic viral infection.⁹ Perhaps the most significant example of this in recent history is the 1918 H1N1 “Spanish” influenza pandemic where an estimated 25 million people died worldwide with hundreds of millions infected.¹⁰ Governments and global health organizations continue to learn from the 1918 pandemic and remain vigilant for signs of emerging pandemic influenza strains.

Infections are also a significant contributor to cancer rates worldwide as the causative agent of approximately 13% of all reported cancer cases.¹¹ Human papilloma virus (HPV) alone accounts for 31% of all infection-related cancers and is the fourth most common cause of all cancers in women.¹¹ It is estimated that 11.7% of women worldwide are infected with HPV and many are reinfected during their life.¹² Recent studies have shown that HPV oncogenicity likely depends on a combination of the viral strain and patient epigenetics.¹³ Although vaccines are available, vaccine hesitancy and difficult distribution in developing countries¹⁴ have caused HPV to remain a common disease with accepted testing methods that have noted issues such as reliability changes with less experienced practitioners.¹³

Mismanagement of infectious diseases and the erosion of trust in the government, healthcare and research organizations

Trust between patients and providers, health-care systems, the pharmaceutical industry and governmental organizations is essential for the healthcare system to function effectively.^15–17 To date, 50% of all trust-related research in healthcare has been in the realm of infectious diseases management.¹⁶ Inappropriate management of infectious diseases is one of the top causes of distrust toward health-care systems. For example, unethical medical experimentation during the Tuskegee clinical trial involved withholding penicillin from Black patients with syphilis to observe the natural course of infection and created multi-generational distrust among Black Americans.¹⁷ Today, the impact of the Tuskegee trial is felt in every aspect of Black American health resource utilization, from low clinical trial participation to vaccine resistance.¹⁷ In China, 250,000 unqualified DTP vaccines were mandatorily administered to children in 2018.¹⁸ This scandal eroded public trust not only in the government and vaccine manufacturers but also in immunization programs. As a result, the anxiety over vaccine safety significantly impeded the public’s acceptance of vaccines.¹⁸

Vaccines have generally been considered safe and effective, and at a population level there are well-established data on the role of broad vaccine coverage on prevention of transmission of certain pathogens. At the individual level, however, a better understanding of host–pathogen interactions and host immune responses reveals that these interactions are very complex and individual vaccines may not be as effective or safe in every patient.¹⁹ To exemplify, inappropriate clinical trial design, rapid approval and premature recommendation of Dengvaxia®, a vaccine against dengue, by prestigious organizations such as the WHO, the Philippines FDA and the Philippines Research Institute for Tropical Medicine, led to the death of 130 Filipino children due to vaccine-induced antibody-enhancement (ADE) of infection and caused massive fear and distrust in the community.²⁰

More recently, the broad politicization of COVID-19 vaccines and treatments led to intense disagreements and divisions in the global community, including scientists, physicians, and government officials.²¹ Sadly, the COVID-19 vaccine hesitancy appears to have spilled over to other vaccines, as pediatric vaccination rates are lower today compared to the pre-pandemic period.²²

Precision in infectious diseases and vaccines is urgently needed to control pandemics & epidemics

Approximately two decades ago, experts challenged the one-dose, one-vaccine fits all approach.²³ The improvement in biotechnology and use of systems biology approaches led to a better understanding of the variability in host immune responses^23,24 and microbial interactions, and made precision vaccinology possible.^25,26 For example, better understanding of viral genetics revealed that egg-based manufacturing of the influenza vaccine may lead to genetic and antigenic changes and ultimately a poor match with circulating influenza viruses.²⁷ Improvements in vaccine manufacturing processes now allow mass production of cell-based influenza vaccines. Better understanding of the host immune responses now shows that repeated administration of influenza vaccines, preexisting levels of hemagglutinin (HA)-specific antibodies and preexisting levels of CD4 T-cells may dampen the post-vaccination antibody gains and vaccine-induced CD4 T-4 cell expansion regardless of the vaccine formulation.²⁸

Finally, during the COVID-19 pandemic, the large variability in vaccine response and safety^29,30 revealed the urgent need for precision vaccinology. The rapid development and widespread use of mRNA vaccines during the COVID-19 pandemic also advanced the technology as an option for precision vaccine design.³¹ Precision medicine in the form of genetic testing and precise health background checks is also useful in determining COVID-19 disease severity³² as several predictive biomarkers and risk factors for COVID-19 severity include gene variants,³³ ACE1 polymorphisms,³⁴ non-O blood types,³⁵ old age, and many comorbidities including obesity and cardiovascular diseases.³⁶ In addition, studies have observed that approximately 10% of the population does not respond well to COVID-19 vaccines. These individuals are most commonly children, older adults, and the immunocompromised. Precision medicine is thereby essential in not only identifying individuals at risk of increased severity, but also in identifying poor or nonresponders using Post-Vaccination Serologic Testing (PVST). Such testing will help to quickly identify these individuals, prioritize them in vaccine rollout, and allow them to receive additional prophylaxis following their full vaccination.³⁷

Every year, Hepatitis B virus (HepB) is responsible for approximately half of all cirrhosis, 80% of liver cancers and 1 million deaths globally. Hepatitis B vaccine has been a breakthrough as it reduced the neonatal Hep B infection and liver cancer and it is recommended globally. However, approximately 5% of those who received two full series of HepB vaccine do not mount a serologic response and become a vaccine “nonresponder.”³⁸ The mechanism behind poor HepB vaccine response is unknown although a number of factors such as old age,³⁹ immunosuppression, chronic diseases like kidney disease, diabetes mellitus, HIV infection,⁴⁰ and a variety of genetic mutations³⁸ play role in poor HepB vaccine response. Precision vaccinology may lead to the development of more effective vaccines or adjuvants³⁸ and precision public health through -omic technology may help identify nonresponders who may then get access to these more effective vaccines.

In the era of precision vaccines, there is also an urgent need for better vaccine safety tracking. At a recent science-of-vaccine safety meeting, the experts identified some of the vaccine safety tracking needs:¹⁹ i) there is a need for a comprehensive and robust multi-country post-licensure vaccine safety monitoring and communication system, ii) real-time media monitoring processes can help regulatory and scientific organizations identify emerging safety concerns and address them quickly;^24,25 iii) human-centered processes that partner with local communities are necessary,¹⁹ iv) pharmacovigilance systems need to be revamped to keep up with the speed of global information exchange and to process the data from rare events,¹⁹ v) reliable monitoring and communication technologies should be developed to detect rare global events from vaccines indicated for smaller patient populations such as pregnant women,¹⁹ and vi) data platforms should be developed to study the interaction between the host immune system, host microbial flora and vaccine components such as adjuvants, antigens, preservatives, DNA/RNA.²⁴

Precision in public health

Precision public health (PPH) is an emerging focus area. It can be described as providing the right intervention to the right population at the right time.⁴¹ The advances in new technologies such as the availability of individual and ethnic level genetic risk information,⁴² socioeconomic data,⁴³ the implementation of artificial intelligence to large medical datasets⁴⁴ and community social media posts⁴⁵ allow better direction of public health efforts to appropriate populations in the most acceptable format. This may lead to precision vaccines for smaller numbers of people and/or patient-groups. Indeed, Dr. Stanley Plotkin who is often referred to as the “Godfather of Vaccinology” emphasized that the next revolution in vaccinology is the development of vaccines for individuals (groups), rather than the population, that currently administered vaccines are not fully protective in certain populations, and that there is a need to evaluate vaccine safety and efficacy in specific populations.²⁶

During pandemics, mass policies are needed to quickly induce immunity among large populations to stop the spread of the pathogen. Early on during the COVID-19 pandemic, the European Commission introduced a vaccination certificate called the “Digital Green Certificate” (DGC) which has been shown to be very effective in slowing down the spread of the virus.⁴⁶ In the United States, the majority of early COVID-19 initiatives focused on large-scale policies like physical distancing, business and school closures, face-mask mandates, and mass vaccination of the elderly and the immunocompromised.⁴⁷ While these policies were effective for decelerating viral spread, hospitalization, and mortality among the most vulnerable, other more targeted and precise approaches, like equitable vaccine delivery, were needed to provide protection for essential workers, for those in low-income neighborhoods and among Latinx and Black communities who were less likely to work remote jobs.⁴⁷ During the early stages of the pandemic, these individuals were largely unprotected by policies like physical distancing and closures and thus, disproportionately affected by COVID-19 disease.³⁰ In addition, a few states in the United States, such as California, implemented precision public health measures, such as mass vaccination events in sports arenas, colleges and designated “hot-spot” zip codes to improve the access to the COVID-19 vaccine.⁴⁷

Recently, Fourati and colleagues conducted a large transcriptomic study (namely, microarray and RNA sequencing) to characterize the host pre-vaccine immune profile that is associated with the strongest antibody responses across 13 different vaccines.⁴⁸ They characterized the pre-vaccination peripheral blood immune transcriptional signature among 820 healthy individuals and observed that there was significant inter-individual heterogeneity in the inflammatory state of the peripheral immune system before the vaccination. They grouped the patients as inflam.hi, imflam.mid and imflam.lo by blood transcriptional signatures and a distinct distribution of cell subsets before vaccination. They observed that people with baseline high level activation of inflammatory genes, specifically those associated with IL-1 and NF-kB signaling, mounted a stronger antibody response.³¹ In this study, the investigators did not evaluate the relationship between the transcriptional signatures and safety signals; however, transcriptomics may also be used to identify individuals who are at higher risk for vaccine adverse effects.⁴⁸

When clinical trials do not provide a sufficient amount of benefit data for a routine age or risk group, the Advisory Committee on Immunization Practices (ACIP) of the CDC may recommend “shared clinical decision-making (SCDM)” for vaccine administration.⁴⁹ During SCDM, the primary care provider and the patient (or parent of the patient) make a personalized vaccination decision based on the provider’s broader knowledge of the patient’s characteristics including risk factors, values, preferences and the family medical background.⁴⁹ The COVID-19 pandemic made it clear that we are moving from “herd” immunity of healthy infants to precision vaccination of smaller groups. Active communication between a trusted provider and the patient/caregiver and SCDM may help achieve precision in public health and vaccines.

In 1892, Sir William Osler stated, “if it were not for the great variability among individuals, medicine might as well be a science and not an art.” Artificial intelligence (AI) has the computational power to collect, analyze and potentially identify the biological and socioeconomic profile of smaller groups within a large community and may be used to support precision in infectious diseases, vaccines and public health. AI, however, has limitations.⁵⁰ Granted that data security and patient privacy are achieved, the quality of data generated by AI is restricted with the amount and quality of input data and quality of the model. Similar to clinical trials, there is a need for data from a diverse range of people from different racial/ethnic and socioeconomic backgrounds, especially vulnerable populations, which is often challenging. AI findings need to be tested and confirmed, but most importantly, new interventions need to be designed and scientifically tested to fully achieve the benefits of AI.

In conclusion, precision in infectious diseases and vaccine development will lead to the development of safer and more effective vaccines, and precision in AI and public health will improve the efficiency and prioritization to deliver the right vaccines to the most appropriate populations, leading to the restoration of trust in vaccines, healthcare, science and public health.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).