Combination vaccines: Probing hurdles and catalysts behind the buzz
By Keely Anderson, Amandeep Singh, Sanket Shelar, Amudha Sharma and Adi Natu
Combination vaccines — Long history of success in the pediatric segment, but rare in the adult space
The first combination vaccines arrived in the 1940s, combining two vaccines commonly given to children for diphtheria and tetanus. Since then, the number of pediatric combination vaccines and the pathogens they address has grown exponentially. More than 20 combination vaccines are licensed for sale in United States, including a hexavalent vaccine, Vaxelis, that targets six pathogens in one vaccine.
Combination vaccines have largely existed within the pediatric space since they emerged. In the 1980s, children would receive as many as 27 shots by the age of two, and up to six shots in a single doctor’s visit. Thus, the Centers for Disease Control and Prevention (CDC) sought to reduce the number of shots required for children in the U.S., and new technological advancements enabled more antigen combinations.
Despite their success in pediatric segment, combination vaccines in the adult space are incredibly rare, and only recently have seen some development momentum.
In this blog, we explore the advantages and disadvantages of combination vaccines, why they haven’t been explored in the adult space until recently, and what vaccines manufacturers must consider as they seek to understand and capitalize on the opportunity for adult combination vaccines within their portfolios.
Figure 1 shows a timeline of combination vaccines entry to U.S. market.
Pediatric combination vaccines — Advantages far outweigh the disadvantages
One of the key advantages and drivers of use of combination vaccines is the convenience benefit that comes from reducing the number of shots within a childhood vaccination program. In the United Kingdom, 11 injections can be given instead of 27, and in the U.S., 24 instead of 70. Additionally, combination vaccines can help increase the coverage rates and series completion rates. This was seen with the inclusion of varicella in the measles, mumps, rubella, and varicella (MMRV) combination vaccine which enabled higher varicella vaccination rates among pediatric patients; coverage with measles- or varicella-containing vaccines increased from 88.36% to 96.55%.
Research and development (R&D) and manufacturing of combination vaccines however is complex, and it is difficult to develop successful candidates. One of the biggest concerns in combination vaccine development is “interference”, where the efficacy of one of the components of an existing vaccine is compromised with the addition of another component. An expert in vaccines R&D that we spoke with mentioned that combination vaccines are difficult to develop as trials are set up to achieve non-inferior efficacy to the existing individual components. Take the pneumococcal conjugate vaccine (PCV)13 as an example, which is meant to have non-inferior efficacy for strains already covered in PCV 7, which is difficult to achieve clinically when adding six additional serotypes to cover. A slight drop in efficacy of the components of the initial vaccine is often considered generally accepted given the fact that the new vaccine could provide protection for additional serotypes and increased immunization rates. This situation is analogous to combination vaccines. It can be difficult to understand how vaccine decision makers might react to the trade-offs of slightly reduced efficacy vs. increased protection and vaccination rates, but for existing pediatric combination vaccines, the trade-off has been in favor of combinations. Across industry this is referred to as “combination-creep” with each further combination, the goalpost moves. The new combination is compared to the most recent combination, which likely has slightly lower efficacy across the original pathogens compared to the standalone vaccines.
Table 1 summarizes the advantages and disadvantages of combination vaccines.
While there is an overwhelmingly positive impression of combination vaccines, the uptake and acceptance does differ across geographies. More than 15 combination vaccines are licensed for use in the U.S., but only six of the vaccines on the schedule in the U.K. are combinations. Nations like China and Japan have less than five combinations included in the National Immunization Programs (NIP). This is attributed to variation in policies for regulatory approval, clinical recommendations, funding and even willingness of patients to pay out of pocket costs.
Regardless, pediatric combination vaccines address a clear unmet need by decreasing shots, increasing compliance, and increasing vaccination rates to prevent deadly infectious diseases in children. While there has been a large benefit from their penetration, what about the adult space? We are beginning to see multiple manufacturers pursuing adult combination vaccines for respiratory conditions, despite similar clinical hurdles. Why is interest building? What hurdles will adult combination vaccines face in the new era? And how can manufacturers set a future adult vaccine candidate up for success?
At least 17 adult combination vaccines in the pipeline, but is the hype and excitement justified?
Figure 2 shows the pipeline of combination vaccines in development.
The COVID-19 pandemic re-emphasized the need for vaccines beyond the pediatric population and created a situation where there is now more overlap across schedule and seasonality of adult vaccines. There are now multiple seasonal vaccines approved for use in adults against respiratory illnesses, such as flu, COVID and respiratory syncytial virus (RSV), that address the “triple-demic”.
Additionally, rapid innovation during the pandemic also brought forward new platforms and technology in vaccine manufacturing and development. Messenger ribonucleic acid (mRNA) and self-amplifying-mRNA with their modular “fail-fast approaches” could make development of adult combination vaccines feasible.
With the advent of these platforms, manufacturers have begun considering the role that combinations can play in lifecycle management of their vaccines that may have been otherwise deprioritized, like the COVID-19 vaccines. These factors, combined with historically low vaccination rates for adults compared to pediatrics, has fueled the recent interest in the space.
Although many experts suggest that combination vaccines for adults could follow a trajectory like that of pediatric combinations, it is important to understand if there is a “burning platform” for adult combination vaccines in the way there was for pediatrics. And, if there isn’t, could there be in the future?
Unmet need: The adult vaccine space has similar unmet needs as the pediatric space a few decades ago; a need for increased vaccination rates and improved compliance and protection. Where they differ is the urgency to reduce the shot burden that exists for pediatrics. Some could argue that there aren’t that many approved and recommended vaccines for adults anyway. But this is changing with the launch of newer respiratory vaccines, which could create a similar shot burden for adults in the future.
Healthcare system buy-in: Regulators and health care professionals (HCPs) were bought in to the need for pediatric combination vaccines, so much so that the CDC announced a preference and interest in combination vaccines. Adult vaccination rates are very low compared to pediatrics, but regulators must be first aware of this unmet need, and second, buy-in to the benefit that adult combination vaccines could provide, especially around increasing vaccine coverage rates.
Adult combination vaccine manufacturers must consider key factors related to clinical feasibility, implementation, and ecosystem engagement to ensure commercial viability
Clinical feasibility: Clinically, adult combination vaccine development poses multiple questions regarding the likelihood of success with single or multi-platform approach, and with or without an adjuvant approach. Assuming the combinations can work scientifically, manufacturers will need to be mindful of interference and combination-creep. Those interested in a respiratory adult combination vaccine are exploring the mRNA platform given its speed, modularity, and dynamic nature to address strain variation and seasonal nature of respiratory viruses. However, this platform is less likely to be able to compete in spaces where protein or adjuvant-based vaccines are highly successful with a long duration of protection. For instance, pneumococcal, human papillomavirus (HPV) or shingles and don’t experience the same mutation and seasonality.
Implementation: Beyond clinical feasibility, choosing pathogens to combine is tricky. Existing vaccines will have their own dosing requirements and will exist as a part of vaccine schedule recommendations on NIPs. Standalone vaccines might be annual, boosters, seasonal or have a much longer duration of protection. Manufacturers will need to carefully plan how the combination of vaccines will impact the dosing and the vaccination schedule and how the combination will fit in terms of administration across components. Strategically, pathogens should be combined in a way to supplement the effect of one another, improving compliance and adult vaccination rates. It is also important to assess how the combination might affect a manufacturer’s existing standalone vaccines both positively or negatively from a financial perspective or even vaccine hesitancy standpoint.
Ecosystem engagement: It will be crucial for manufacturers to engage with the vaccines’ ecosystem early in establishing the disease burden and unmet needs. Manufacturers should assess where the unmet disease burden exists and what the regulatory potential would look like from national immunization technical advisory groups (NITAGs). Additionally, it is critical to provide consistent messaging to ecosystem stakeholders around how the combination with address convenience — an operational barrier — in a way that impacts health economic burden. These activities will directly affect the perceived unmet needs and the perceived impact of a combination adult vaccine. Regulators, NITAGs, distributors, payers, providers, and patients will all play a role in the success of an adult combination vaccine, meaning it is crucial to understand their expectations and requirements for success.
What should we expect in the long-term?
A tremendous untapped opportunity lies ahead in the combination space. Candidates for multiple indications in different demographic segments could be explored, and, although respiratory combos represent a minor piece of the enormous white space, these may be the first successful adult combination vaccines to market. It is expected that this market will follow pediatric combos, where combinations emerge based on what is available, likely starting with a COVID and flu combination, followed by a COVID, flu and RSV. With these viruses, the manufacturers with mRNA capabilities are likely to have the upper hand. Many manufacturers are exploring similar combinations, like adult respiratory vaccines, and will need to have a realistic perspective on how to differentiate their combination from other emerging competitors.
Manufacturers will need to also closely consider how combinations could impact their existing assets to avoid cannibalization. A manufacturer with a successful standalone vaccine is unlikely to consider it for a combination, unless necessary to protect against a future competitor, or as a lifecycle management strategy. Players might consider how combinations could combat less preferred recommendations of a standalone vaccine, such as a shared clinical decision-making recommendation by the Advisory Committee on Immunization Practices (ACIP) in the U.S. These players will also look at how combinations might improve a standalone vaccine’s payment coverage, such as whether a vaccine is private pay such as in Japan, which can hinder volumes, or covered under Medicare Part B in the U.S., which can greatly improve vaccination rates.
Regardless, there is much interest to see what’s next for adult combinations vaccines, whether pneumococcal and RSV or shingles; Guillain-Barré syndrome (GBS) and RSV maternal or if others will emerge. Similarly, it remains to be seen if options in immunocompromised patients or for hospital inquired infections will be explored. We are in for a few interesting and exciting years ahead in this field!
References:
1. Pubmed
3. Researchgate
5. CDC
