From a global public-health standpoint, vaccines are considered some of the most important inventions in human history. Some notable achievements of vaccines include the eradication of smallpox and the near eradication of poliovirus. Approximately 300 million people died of smallpox between 1900 and 1980, and millions more were disfigured; however, by 1979, vaccination programs had completely wiped out the disease.1 In 1988, at the onset of a global campaign to end polio, there were 350,000 new cases per year; nearly 30 years later, only 22 cases were reported, and those were in war-stricken areas where immunization was not possible.2
The past 20 years have seen a rejuvenation of innovation in vaccines, including vaccines for pneumococcus, rotavirus, human papillomavirus (HPV), and varicella. Indeed, in the 2017 annual letter, the Bill & Melinda Gates Foundation reported that 122 million children’s lives had been saved since 1990—and that vaccines were the biggest reason for this decline in childhood deaths.3
These statistics are in line with the historically high growth rate of the vaccine industry—12 to 15 percent year on year over the past two decades—which is double the rate of the rest of the pharmaceutical industry.4 In the past ten years, the number of vaccines in the pipeline has also doubled, to 336 vaccines in 2017.5 And while vaccines have mostly focused on disease prevention to date, we expect them to play an increasing role in treatment (for example, treatment vaccines for HPV and hepatitis B) and thus have even greater impact in the future.
However, we have seen four signs of slowing innovation over the past five years:
1. Revenue growth has slowed to below 5 percent in the past five years (Exhibit 1, click through the interactive).
2. We are now seeing a flattening development pipeline (Exhibit 2, click through the interactive), with the share of growth from new vaccines launched down from almost 50 percent in 2011 to less than 15 percent in 2017—the lowest level in 20 years (Exhibit 3, click through the interactive).6
3. We are recording higher attrition rates for vaccine-development programs relative to other biologics, with “fewer shots on goal,” meaning fewer vaccine candidates are advancing to clinical studies (Exhibit 4, click through the interactive).7
4. There are remaining unmet needs cutting across multiple categories of vaccines, including diseases endemic to high-income regions (such as HIV and norovirus) and those endemic to low-income regions (for instance, tuberculosis and malaria).
Historically, the “Big Four” global vaccine manufacturers (that is, GlaxoSmithKline, Merck, Pfizer, and Sanofi) have driven most innovation. However, in the past five years, their pipeline growth has been flat, and the majority of new programs in the pipeline have been driven by emerging-market players with “me too” vaccines (that is, vaccines undifferentiated from those already on market) and by smaller biotechs (Exhibit 5).8 While there is potential for significant innovation from biotechs, there is an open question around whether sufficient absorptive capacity exists in the system to bring these programs through development. Indeed, our observations on the pharmaceutical industry suggest that manufacturers vary broadly in their abilities to identify, acquire, and gain from external innovation.
The external market expects a return to growth, with analysts forecasting 6 to 9 percent growth in the global vaccine market over the next five years.9 In addition, there is considerable potential for new antigens as well as novel synthetic modalities (for example, messenger-RNA-based products). Inherent in these market assumptions are the successful Phase III completion of several vaccines in development as well as further advancements in innovation. The key question is whether the vaccine industry can overcome several challenges that are currently affecting innovation.
Challenges to innovation in vaccines
Our research on industry trends suggests reinvigorating vaccine innovation will require addressing three underlying issues:
- increased investment requirements for mid- and late-stage R&D and manufacturing
- increased opportunity cost as relative investment economics converge with other biologics
- higher technical complexity and commercial uncertainty compared with recent innovations
These challenges have the potential to affect different categories of vaccine manufacturers in different ways. On one side, they could create opportunities for innovation by new players. On the other side, they may create structural barriers that offer an advantage to existing players.
Increased investment requirements for R&D and manufacturing
Emerging trends contributing to a progressively challenging environment for innovation are the increases in investment requirements for R&D and manufacturing. These shifts in the broader infrastructure affect the overall economic equation of the vaccine industry by increasing the length of time and the costs associated with innovation.
On the R&D side, regulatory scrutiny, overall, is on the rise across more complex products (for example, biologics, vaccines, and other sterile injectables), with longer timelines for vaccine approval (Exhibit 6).10 Also, given the preventive nature of these drugs, vaccines face a heightened bar for quality and safety, which thereby adds both complexity and additional cost throughout the development process.
In addition, many of the pipeline programs have lower incidence rates than in prior vaccine innovations and thus face evolving clinical-trial requirements. Clinical trials need to elicit a strong and lasting immune response and require a natural incidence of the disease where the trial is being conducted. Developing a vaccine for diseases with a lower incidence requires many more participants and sites to demonstrate efficacy, increasing both the cost and the duration of the trials.
On the manufacturing side, we have seen shortages, recalls, and other manufacturing challenges in recent years. Recent examples include recalls of typhoid and varicella vaccines because of efficacy concerns as well as shortages and prequalification removals for pediatric combination vaccines because of manufacturing-reliability issues. These issues have resulted in lost sales and significant investment requirements to transform vaccine-manufacturing networks.
Increased opportunity cost as relative investment economics converge with biologics
Increased technical challenges are resulting in the convergence of the success rate of bringing vaccines to market with that of bringing other biologics to market. However, given the higher revenues derived from blockbuster biologics compared with vaccines—for example, the largest biologic’s revenue is more than two to three times greater than the largest vaccine’s revenue (pneumococcal conjugate vaccine had peak revenue of $6 billion)11—this convergence of success rates reduces the relative attractiveness for investment in vaccines compared with the past, especially as the largest global vaccine manufacturers all have competing priorities. As pharmaceutical companies allocate capital to opportunities with the highest returns on investment, this change in the relative investment economics will be a consideration in future decision making for vaccine innovation.
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Higher technical complexity and commercial uncertainty compared with recent innovations
Many vaccine-industry leaders consider the recent major innovations (such as pneumococcus, rotavirus, and HPV vaccines) to be lower-hanging fruit in immunization—these vaccines had high commercial potential and higher relative technical feasibility. The remaining potential innovations face increased commercial uncertainty and technical complexity in an environment of increasing R&D and manufacturing investments, as previously described.
From a commercial perspective, the pipeline of remaining innovations has a different profile (Exhibit 7)—the absolute size of relevant populations is smaller, and the programs have less established pathways compared with pediatric or adolescent vaccines, which have recommended immunization schedules. In this context, capturing the full market potential still requires navigating a complex vaccine care flow that has many influences and inputs (Exhibit 8). Obtaining the recommendation for inclusion in immunization schedules is the most uncertain step, as vaccine manufacturers typically have limited visibility on what recommendations to expect. This step is critical to securing reimbursement and access to markets, so the situation builds additional uncertainty related to return on investment for vaccine manufacturers. Also, once a vaccine is on market, capturing market share requires navigating a broad set of stakeholders (physicians, retailers, payers, and patients), often with uncertain pricing and market demand contributing to additional commercial risk.
Regarding technical feasibility, the remaining pipeline innovations are challenging. In particular, potential blockbusters are often long-sought-after vaccines that have been tried (and failed) multiple times in the past (for example, HIV and universal flu vaccines).
Stepping back, as the sources of growth shift from relatively low-hanging fruit to new opportunities for innovation, we see six vaccine archetypes emerging with varying levels of technical complexity and commercial opportunity (Exhibit 9):
1. High-income markets. Vaccines can target diseases in high-income markets, including healthcare-acquired infections (for instance, Clostridium difficile and staphylococcus infections), as well as other disease areas (for example, norovirus). These programs have moderate technical feasibility but vary in commercial potential. For example, nosocomial-infection vaccines have high market potential but unclear commercial models and indications (for instance, they may not have clear immunization schedules), whereas other vaccines for high-income markets have moderate commercial potential and a mix of potential commercial models.
2. Potential blockbusters. Vaccines can target high-burden diseases with large global potential patient pools (such as HIV and respiratory syncytial virus) carry a high commercial potential. Pregnant women, for example, make up a population with significant unmet need remaining in immunization. Challenging technical complexity results in low to moderate technical feasibility for these innovations.
3. Treatments. Vaccines can be used as methods of treatment to fight existing diseases or conditions, rather than as preventative measures. Potential applications for these vaccines include oncology and smoking-cessation, as well as infectious-disease treatment. High unmet need results in a high commercial potential for these programs, but technical feasibility is low to moderate.
4. Incremental improvements. Improvements to existing vaccines can address unmet needs (for example, improvement in efficacy, duration of protection, and ease of use). While technical feasibility for these programs is moderate to high, the commercial value is uncertain, particularly in assessing the prices these incremental innovations can command.
5. Emerging threats. Vaccines can target emerging epidemiology threats and future priorities for innovation (for instance, Ebola virus and Chagas disease). These programs have an uncertain commercial demand profile, given the lack of clarity on the willingness of governments and agencies to stockpile significant amounts or pay more than “costs” to maintain supply options. The technical feasibility is moderate and varies by disease.
6. Low-income markets. Vaccines can target diseases with higher burden in low-income markets (for example, tuberculosis and malaria) with moderate commercial potential and significant technical challenges. The evolution of supply and demand for vaccines in emerging markets creates significant ambiguity, compounded by the entrance of new local players. In addition, as Gavi countries (developing countries that receive support from the Gavi public–private partnership to increase access to vaccines) transition to take over responsibility for financing vaccine programs, growth in those emerging markets may slow—as experienced in Angola and the Republic of the Congo, where the governments have struggled to meet their cofinancing requirements in recent years.
Where do we go from here?
Given the commercial and technical challenges and the criticality of vaccines in advancing public health, continued innovation in the vaccine industry can best be supported via a comprehensive and shared agenda across key stakeholders: researchers, manufacturers, governments, policy makers, and payers. Several potential solutions might contribute to refueling the vaccine innovation engine.
Demand clarity
Earlier clarity on market demand would provide increased commercial certainty for vaccine manufacturers by helping to identify the priority innovations to address unmet market needs. One potential method might be to publish target-product profiles on the desired innovations. In addition, the profiles could include advance recommendations that would clarify likely recommendation or use given a specific profile, which would be particularly relevant for innovations in high-income-market, nosocomial-disease vaccines (archetype 1), as well as for innovations in treatment vaccines (archetype 3).
Value communication
Stakeholders could consider becoming more active in articulating priorities and value associated with material improvements to an existing standard of care (for example, addressing whether an improved Haemophilus influenzae type B vaccine would achieve market premium and whether universal flu vaccines are adequately valued). This improved transparency would be particularly relevant for innovations addressing incremental improvements in vaccines (archetype 4) as well as potential blockbusters (archetype 2).
Economic incentives
One potential approach to creating incentives for innovation is to facilitate funding for new models of industry partnership for both emerging threats (archetype 5) and low-income-market unmet needs (archetype 6). CEPI has made noteworthy progress in building alliances to finance and coordinate the development of new vaccines to prevent and contain infectious-disease epidemics. However, as CEPI primarily focuses on early-stage development (through Phase II clinical trials), additional solutions are still needed to address the challenge of funding the high-cost late-stage development.
Collaboration and data sharing
Improving transparency and data sharing could be valuable in overcoming technical challenges and achieving breakthroughs where they are most needed. Public–private partnerships may be particularly relevant for archetype-4 innovations, such as vaccines for HIV, tuberculosis, and malaria treatment. In such cases, significant need remains, but there are critical technical challenges, and the expected economics do not currently warrant industry leadership. A second form of collaboration could be to develop new technology platforms that enable shared production across antigens; this would be particularly valuable for emergency-response innovations (archetype 5) to enable rapid scale-up. A third could be to generate more data around the burden of disease for pathogens that may be emerging or simply poorly understood. Finally, enhanced clarity on the public end-to-end vaccine and immunization agenda—from funding early research to trial design and preferred clinical-trial-site networks and, ultimately, to approval and market access—could boost innovation.
Early consultation on innovation design
Manufacturers could seek early and active engagement with regulatory and recommendation agencies throughout the development life cycle of new vaccines to obtain timely input to key decisions, including trial design. This could help to derisk the commercial uncertainty of innovation.
After a period of significant growth over the past two decades, vaccine innovation faces several challenges—namely, increased investment requirements for R&D and manufacturing, higher opportunity cost as relative economics converge with biologics, and greater technical complexity and commercial uncertainty compared with recent innovations—going forward. However, we believe there remains significant opportunity for vaccine manufacturers and other stakeholders (regulators, policy makers, and payers) to facilitate the next wave of vaccine innovation.
