Vaccine developers are currently under pressure as the uptake of vaccines falls in most middle and high-income countries as a result of negative comments in press articles or misinformed social media exchanges. This downplaying of the benefits and exaggeration of adverse events associated with vaccination programs has coalesced into an “anti-vax movement.” Diseases such as measles that public health scientists had considered well on the road to eradication, similar to rubella and mumps, are re-emerging, which is unexpected given the proven safety and efficacy profile of existing vaccines.

The general public needs to be better informed as to relevant risk/benefit analyses for such decisions concerning personal safety as they may have lost the historical knowledge regarding the impact of vaccine preventable infectious diseases such as poxviruses/polio and measles. Individuals may therefore put more emphasis on the risk part of such analyses as being more tangible. Additionally, of on-going concern is the rise of vaccine resistance due to religious beliefs, with falls noted in childhood vaccinations. It is largely thanks to childhood vaccination and wider public health programs that smallpox has been eradicated, polio is on the verge of extinction, and that global levels of pulmonary tuberculosis are falling at the rate of 2% per year; although this needs to accelerate to 4–5% to achieve the 2020 milestones of the End TB Strategy.

Despite material advances in public health and substantial investments into improving the quality of life for all, at a minimal price per dose, the vaccine and wider pharmaceutical industry does not feel able to celebrate its successes due to the perceived risk of a minority backlash and not least, because it is difficult to celebrate an absence of disease. This sentiment is in sharp contrast to the broad social acceptance and appreciation of antibiotics—the effects of antimicrobials are obvious as they cure a tangible, frequently visible illness. Such is the reliance and ingrained nature of antibiotic usage in the public mind and clinical practice that there is more concern regarding the rise of anti-microbial resistance (AMR) than the threatened loss of herd-immunity to preventable diseases.

As vaccines primarily prevent an illness initiating or worsening, it is perhaps understandable that coincident illnesses occurring around the time of vaccination are given credence as a side-effect or adverse event associated with the vaccine by some, especially since peaks of disease are seen in the very young and the elderly when vaccination programs are also prioritized. A clear understanding of vaccines and their uses and benefits is essential if we are to recognize the successes of vaccination and promote eradication and control programs at all levels.

The Immunology of Vaccines
To support advancements in antigenic priming, especially in the very young, the industry needs access to better immuno-stimulatory and modulatory agents. Alum retains its number one position as the adjuvant of choice for many vaccines as many of the emerging adjuvants are difficult to manufacture or hard to access e.g., QS-21 from the soap bark tree in Chile. More study is also needed into the immunological action of adjuvants in specific populations, especially in those for whom vaccines can be less effective, to improve responses.

Vaccines that target enteric bacteria, such as the recently licensed cholera vaccine, Vaxchora (a live attenuated cholera bacterium suspension), typically only show limited efficacy (≥80% at 90 days) and protection is often short lived. The same might be said for influenza vaccines, which only confer protection for twelve to eighteen months, demonstrating the problems associated with mucosal pathogens and inducing protective responses. Studying the role of innate and adaptive immunity in enteric disease may thus provide insights into infective agents of the respiratory tract and shared correlates.

Pressing Disease Needs
The larger ongoing governmental and not-for-profit programs extant across the globe highlight the most pressing needs in terms of public health interventions and give some visibility of the scale of the problem. For example, the seasonal influenza vaccine, as recommended by the World Health Organization, has not reached expected levels of efficacy (>60% average across all ages) over the past 5-10 years, therefore, vaccines that give an improved breadth of coverage (strains and geography) and protection (incidence and longevity) are essential. Another flu pandemic is inevitable and while there is some consensus that, based on historical evidence, it may be caused by a reassorted H1N1 strain, this is by no means certain. It might equally be an H3N2 or H2N2 pandemic and it is not impossible that it will come from an avian virus that has yet to consistently cross into humans e.g. H5N1 or H7N9, although there is no historical evidence that an adaptation of a highly-pathogenic avian influenza virus to humans e.g. via pigs, is imminent or indeed possible.

The last pandemic virus, pdmH1N1/09, emerged in 1998 as the North American triple reassortment internal genes (TRIG) strain but was not identified until 2015 despite repeated H1N1/H1N2 infections in humans from 2005 to 2009. Indeed, the assertion by key opinion leaders in 2008 that: “…. the question arises whether the next pandemic (is limited) to only H2 viruses in the near future. The majority of the world’s population (younger than 40 years) has no protective immunity to H2 subtype influenza viruses that circulated between 1957 and 1968…” failed to identify pdmH1N1/09 as the next pandemic influenza strain. This illustrates that even expert predictions can be inaccurate. Epidemic modeling programs are also prone to error even at geographically-limited, local levels, with peak incidence and virus strain (prevalence and timing) the most common outliers.

All the above leads the vaccine industry to struggle with correctly targeting strains in a timely manner and with culturally acceptable approaches to infectious disease intervention and prophylaxis.
Another viral pathogen with a high disease burden is the Respiratory Syncytial Virus (RSV). RSV is much underserved in the pediatric population with lower respiratory tract (LRT) infections seen in 4-5 million children annually and more than 125,000 children admitted in the same period for RSV-related illness. The recent failure during Phase 3 trials of the Novavax post-fusion antibody-inducing vaccine was a huge setback and whilst MedImmune’s monoclonal antibody palivizumab (Synagis) has proven preventative properties, at-risk individuals require monthly dosing throughout the RSV season and, as with most large-molecule biologics, is complex and thus expensive to manufacture. An effective, long-lasting RSV vaccine would be hugely beneficial to both pediatric and elderly populations, especially in low and middle-income (LMIC) countries which suffer the highest rates of morbidity and mortality.

Modeling Disease to Improve Disease Interventions
Both influenza and RSV lend themselves, to modeling in controlled environments, as do many other respiratory viruses. The controlled human infection model (CHIM) is increasingly utilized to provide efficacy data before moving into later-phase field trials. In vaccine CHIM studies, subjects are dosed or ‘challenged’ with infectious titers of the virus of interest following vaccination and the rate of infection (attack rate) and number and severity of symptoms noted. Such challenges take place within a containment facility to avoid accidental release of the agent into the environment and subjects are monitored and sampled intensively to gather contiguous data regarding both the infectious agent and disease state with an emphasis of subject safety. The CHIM model is being employed to explore other infectious agents; viral, bacterial and even parasitic.

Malaria is a complex, often intractable disease, and with a rapidly warming climate, areas where malaria-carrying mosquitos are endemic are set to expand. There is a big push from concerned organizations such as the Gates Foundation and the US National Institute of Allergy and Infectious Diseases (NIAID) for accelerated translational research into malaria vaccines and, in the absence of an effective correlate of protection, the development of the Controlled Human Malaria Infection model (CHMI) in the US and Europe has led to such modeling in controlled environments becoming one of the primary investigatory tools in the developmental process. CHMI allows studies to be carried out not only in Western, immuno-naïve cohorts, but also in endemic areas where exposure, often due to long-term or serial infections, is commonplace, thus providing evidence for prime and boost properties to be assessed with a high margin of safety and predictive value of efficacy in the field.

Epidemics, Pandemics and Outbreaks
With the rise of anti-microbial resistance and multi-drug-resistant tuberculosis, vaccines are seen as offering real potential in controlling certain acquired bacterial infections. Where approved anti-bacterial vaccines exist e.g., meningococcal meningitis, they can be far more effective than antibiotics in reducing disability-adjusted life years (DALYs), a commonly used measure of disease burden. Pneumococcal vaccines in particular, have been very successful at preventing meningitis and sepsis in specific pediatric populations (<2 years old), but, as catastrophic outbreaks of childhood disease are now so rarely seen, there is the risk of complacency, particularly alongside the rising fear of vaccination.

The Importance of Improving Challenge Modeling
The development of challenge agents (CA) to current Good Manufacturing Practice (cGMP) has allowed studies to be performed using well characterized pathogens possessing the same level of purity and safety as demanded for commercial drugs and vaccines. Challenge agents are designed and manufactured to preserve wild-type characteristics and thus emulate natural disease, but with a higher infection rate and a consistent spectrum of symptomologies. Combined with a pre-screened population of healthy volunteers the result of such controlled infections is low-noise data i.e., observations and measurements unencumbered by comorbidity or coinfection effects and where the point of initiation and recovery are both known. During challenge studies the disease state can be monitored alongside correlates such as humoral markers e.g., antibodies or viral or bacterial shedding or blood parasitaemia (malaria), to provide meaningful data regarding endpoints and outcomes.

In the general public, comorbidities and co-infections are common and may be difficult to compensate for. Challenge studies in healthy populations, screened to exclude those subjects with pre-existing disease, are able to provide highly relevant data including estimates of efficacy and limited safety data (due to small cohort sizes)early in the development cycle and such data may further inform vaccine candidate choices and drug dosing regimens.

Both inherent and acquired properties of challenge agents, for example changes induced during the manufacturing process, may have direct bearing on the quality of clinical trial results downstream. A number of historical challenge agents suffered from low attack rates at even very high titers (relative to community acquired infections), demonstrated low or intermittent shedding during infection, or resulted in insufficiently pronounced symptoms. Given current CA limitations, researchers utilizing CHIM modelling need access to improved agents that are more representative of those viruses circulating in the community if derived data is to translate into effective therapies in the field. Such agents should offer virulence with parity to wild-type virus and a significant range of symptoms.

Although the challenge model has achieved a substantial degree of standardization through shared data and debate in the CHIM community, a number of elementary questions remain unanswered such as the low incidence of fever in influenza studies. By adapting CHIM to better mimic real-world disease, it should be possible to improve the predictive value of early phase studies and reduce the number of late phase failures.

Improving the efficacy of challenge agents requires the assistance of regulators to specify guidelines within which the end users (academia/industry) can work and standards to conform to. Currently, when releasing a new challenge agent as fit-for-purpose, the qualified person (QP) has no specific guidelines within cGMP nor quality standards to adhere to. Each challenge agent’s manufacturing plan is considered on a case-by-case basis by the local regulatory authority with only vaccine manufacturing guidelines available for reference. Live vaccines differ materially in many aspects from challenge agents, not least in the need for the retention of virulence and pathogenesis in CAs. Demands to meet vaccine standards may mean the resulting agent is so avirulent that it is incapable of generating disease correlates necessary. To enable the better use of CHIM to accelerate pipelines, a larger menu of antigenically relevant challenge agents is required. Currently there are only approximately 10 influenza strains in common use, all of which are type A.

The Hunt for Better Correlates
Amongst many infectious diseases e.g. influenza, RSV and tuberculosis, there is a concern that a lack of relevant correlates which inform outcomes and endpoints, will lead to delays in the development and approval of new drugs and vaccines. The development of new vaccines is accelerated where reliable correlates of protection (CoP) are available, especially those that provide reliable translational evidence, from animal models through to first-in-human trials and beyond. However, frequently there may be no known CoP, or correlates may show unacceptable strain variability, and not equate to an endpoint.
Additionally, markers may be non-functional, thresholds for individual versus community protection may differ widely (for example adult and paediatric thresholds) or seroprevalent markers may reflect natural immunity and not inferred or induced responses. Where correlates are measurable and/or quantifiable, values may suffer from intra and inter-assay variability, and   markers may lose prognostic effect over time, may work as complexes, or simply fail in the face of genotypic or phenotypic changes in the target organism. All of which lead to the need for more basic research and a greater understanding of relevant correlate.

When assaying immune responses to new and existing formulations, it has become apparent that antigenic dosage may not be as important as the reactogenicity, as measured by priming of the immune system and longevity of response. Thus, imprinting at an early age with antigenically relevant, adjuvanted or highly antigenic formulations may preserve recall and efficacy during future challenges. As a final thought, recent evidence suggests that repeated vaccination, with antigenically similar preparations, may actually downregulate the protective antibody responses. This poses questions for the seasonal influenza vaccine but may also lead to improved formulations; often only by asking difficult questions do we find answers to difficult problems.