From a pharmacoeconomic perspective, vaccines are arguably one of the most cost-effective interventions available, to reduce healthcare and hospitalization costs, as well as mortality/morbidity and worker productivity issues. One study indicates that among US children born during 1994– 2013, vaccination will prevent an estimated 322 million illnesses, 21 million hospitalizations, and 732,000 deaths over the course of their lifetimes, at a net savings of $295 billion in direct costs and $1.38 trillion in total societal costs. 
A handful of vaccines that target viral or bacterial infections are also known to reduce the incidence of cancers that are associated with those infections. This is the case hepatitis A and B vaccines (which have reduced the incidence of liver cancer) and vaccines against human papilloma virus (HPV), the leading cause of cervical cancer and certain oral, vaginal and anal cancers, as well. Separately, concerted effort is underway to develop vaccines that are explicitly aimed explicitly at preventing certain types of cancers and tumor types.
Once almost an afterthought in drug development, vaccine franchises are now a viable source of revenue for companies that are willing to go the distance with them. And when it comes to pursuing vaccines to protect people against infectious and other neglected diseases in tropical and sub-tropical nations, development efforts also provide a source of altruistic and humanitarian pride, despite the lack of traditional market and profit incentives.
The developmental pathway for vaccines is far from straight or clear — in terms of uncertainty associated with the underlying science, multi-faceted manufacturing challenges, cold-chain distribution and storage obstacles, and lingering mistrust and fear-mongering among a small but outspoken group of skeptics. As such, the ROI for any given vaccine-related venture is anything but assured. Nonetheless, due to unmet medical need, the overall world vaccines market is predicted to grow from $34 billion in 2017 to $49 billion by 2022, at a CAGR of 7.5%, according to an August 2017 study from market-research company MarketsandMarkets.
Traditionally, vaccines were consigned to the pediatric sandbox. However, in recent years, there’s been strong growth in the development and use of vaccines aimed at adult populations. These include modern vaccines against:
• human papilloma virus (HPV)
• pneumococcal pneumonia and meningococcal diseases (including meningitis)
• shingles (herpes zoster)
• hepatitis A and B
• seasonal flu (influenza)
“One of the challenges for penetrating this largely untapped adult patient population is that people age 18–49 are generally healthy, so they don’t always see the value of getting vaccinated against a disease they have not yet encountered,” says Nitin Mohan, Vaccines Therapy Area Lead for IQVIA. “Healthy patients often say ‘Why should I pay $300 for a vaccine that may only be 50% effective?’ This raises the stakes for vaccines aimed at the adult market — to produce vaccines that are most effective and most affordable.”
Today, “the Big Four” in vaccine-manufacturing scene—Pfizer, Merck, Sanofi Pasteur and GlaxoSmithKline (which acquired Novartis’ vaccines business in 2015)—have proven that there is strategic value in vaccine franchises. In 2017, they posted these worldwide vaccine-sales figures:
* Sanofi Pasteur — $6.2 billion (up 8.3% from 2016)
* GlaxoSmithKline — $7.24 billion (up 6% from 2016)
* Merck — $6.5 billion (up 4.8% from 2016)
* Pfizer — $6 billion (down by 1% from 2016)
And the slate of smaller, specialized biopharma companies pursuing various vaccines also continues to grow.
The pharmacoeconomic impact of vaccination
When it comes to making the pharmacoeconomic case for a given vaccine, drug developers are increasingly working to demonstrate the full value of the vaccine program — including cost savings that come from avoiding secondary health impacts associated with the vaccine-preventable illness. Some recent studies provide compelling evidence to help justify vaccine prices and payer-coverage decisions:
* Increasing childhood vaccination in pneumococcal disease, meningitis and rotavirus would be valued at over $63 billion. 
* Increased use of the seasonal flu vaccine can decrease the risk of myocardial infarction and stroke risk in older patients, among studied patients 
* Pneumococcal vaccination is associated with a 50% lower risk of myocardial infarction two years after vaccination, among studied patients 
* People who developed shingles (herpes zoster) had increased risk of heart attack (60% higher) and stroke (35% higher) compared to those who were vaccinated to prevent shingles;  this study also suggested that getting shingles raised patients overall risk of having a cardiovascular event by 41%, mirroring the findings of an earlier study 
Shape-shifting market dynamics
Where blockbuster sales potential is forecast for successful vaccines, the old adage applies: “To the winner go the spoils.” This has created an arms race among vaccine developers who race to commercialize a first-in-class immunization option, and those pursing next-in-class entrants that must demonstrate clinical advantages to capture some market share of their own.
In recent years, the fortunes of many pediatric and adult vaccines have risen and fallen quickly as a function of market dynamics in three areas:
* breakthroughs in vaccines for a growing number of disease states
* expansion of formal immunization programs in a growing number of countries
* expanded prescribing indications, and “preferred-status” recommendations from the US Centers for Disease Control (CDC), Geneva-based World Health Organization (WHO) and others (related to which vaccines should be favored in a given indication due to clear clinical advantages)
The four case examples discussed below showcase how quickly a change in one or more of these drivers can create a reversal of fortune for a leading vaccine franchise.
Case #1 — pneumococcal pneumonia and meningitis. Pneumococcal meningitis causes deafness and brain damage and kills one child in 10 who get it, according to CDC, which notes that since the introduction of Pfizer’s Prevnar 13 breakthrough vaccine to protect against it, severe pneumococcal disease in children has fallen by 88%.
Meanwhile, 300,000 or more adults (age 50 and older) are hospitalized each year for pneumococcal pneumonia, according to FDA, and roughly 18,000 older adults die from pneumococcal disease each year in the US, according to CDC data. Some strains experience antibiotic resistance, making prevention through vaccination more important than ever.
Pfizer’s leading vaccine, Prevnar 13, is used for the prevention of 13 of the most serious types of pneumococcal pneumonia and meningitis. Initially, it was approved for use in younger patients (6 weeks to 17 years of age), and older patients (aged 50 and over). However, in July 2016, Prevnar 13’s indication was expanded, allowing patients aged 18 to 49 years to receive the vaccine, and this helped to grow market share considerably. Expanded indications helped the vaccine’s global sales in 2017 to reach $5.6 billion.
Merck has its eye on this lucrative market with its own investigational pneumococcal conjugate vaccine (V114). Now in phase 2 trials, this vaccine protects against 15 serotypes, so if approved, it could provide broader coverage — and thus competitive advantage — over for Pfizer’s Prevnar 13 to prevent pneumococcal infections.
Case #2 — Upheaval in shingles prevention. Over the past year or so, a mix of clinical and market drivers has created a swift reversal of fortunes for Merck’s first-in-class Zostavax shingles vaccine in favor of GSK’s later-arriving Shingrix vaccine. Shingles — which produces a blistering rash and post-herpetic neuralgia that can last for weeks or even months (leaving ulcers and scars).
Shingles occurs in adults who had chicken pox (varicella-zoster virus) as a child; that insidious virus remain dormant in the body and can reappear later as shingles, as the immune system weakens with age. In the U.S. alone, more than a million cases of shingles occur each year, and according to CDC, one in three adults can expect to develop the condition during their lifetime.
Merck’s Zostavax, a live vaccine that is given in a single injection — was approved in 2006, and has long been the only option for preventing shingles. Zostavax generated global sales of $668 million in 2017. While the vaccine has certainly provided a shot in the arm in terms of greatly reducing the incidence of shingles, it does not provide blanket protection, but instead reduces the incidence of shingles in adults who had chickenox as a child by 50–70% depending on the age of the patient, according to Merck.
By contrast, the newer option — GSK’s Shingrix vaccine, approved in October 2017 — is a non-living vaccine formulated by using a section of the virus to stimulate immune response. Given in two doses (2–6 months apart), Shingrix reduces the incidence of shingles by 98% in the first year, and that protection remains at 85% or higher three years after vaccination, according to the company. Meanwhile, Shingrix is approved for a younger patient population (aged 50 and older, compared to “60 and older” for Zostavax).
And importantly, Shingrix is approved for use in patients who have a compromised immune system (due to HIV, steroid use, transplants or chemotherapy), because it is a recombinant vaccine made from a glycoprotein and adjuvants. Such patients are precluded from getting the Zostavax shot (because it was made with a live virus), per its FDA label indication.
Adding wind to the sails of the Shingrix franchise, in October 2017, CDC’s Advisory Committee on Immunization Practices issued a preferential recommendation for Shingrix over Zostavax for shingles prevention, and the European Medicines Agency quickly followed suit in January 2018. Sales of Zostavax have been slipping ever since, falling by 45% in the fourth quarter of 2017, to $121 million, according to Merck.
According to the economic-forecasting firm EvaluatePharma, worldwide sales of Zostavax are expected to fall from $729 million this year to just under $600 million by 2022, while at the same time, Shingrix sales are projected to reach $1 billion/year by 2022.
Case #3 —A tense ‘pas de deux’ in HPV and cervical cancer prevention. The direct link between vaccination to reduce infection from the sexually transmitted human papilloma virus (HPV) provides a compelling clinical and marketing advantage for HPV vaccines. In 2017, Merck’s first-in-class Gardasil vaccine franchise generated global sales of $2.3 billion (growing by 6% over 2016 sales).
While Gardasil was first approved in 2006, and Gardasil-9 (which protects against all 9 strains of HPV virus) was approved 2015, GSK’s later-arriving HPV vaccine Cervarix (FDA approved in 2009) has tried valiantly — but unsuccessfully —to make inroads against Merck’s juggernaut HPV vaccine in the US and Europe. In mid-2016, citing “very low market demand,” GSK pulled its Cervarix HPV vaccine from the US market, ceding the entire HPV market to Merck in these two regions.
In an effort to increase HPV vaccination rates, CDC revised its dosing recommendations for Gardasil (now the only available HPV vaccine in the US) in September 2017, from the traditional three-shot regimen to just two shots for girls and boys who start the regimen before their 15th birthday (patients 15 or older are still recommended to get three shots of Gardasil), a move that is likely to negatively impact sales revenue for Gardasil, according to several analysts.
However, Merck’s overall market potential for Gardasil still has a lot of room to grow. Within the US, HHS has set a goal of 80% for adolescents of both genders by 2020, but CDC data shows that in 2016 only 60% for U.S. teens (age 13 to 17) received at least the first dose of HPV vaccination, and only 43% of all teens received the second shot to complete the recommended vaccination dosing.
Meanwhile, seeking to salvage its Cervarix franchise, GSK has set its sights on China — where cervical cancer is reportedly the third most common cancer among women aged 15 to 44, with 100,000 new cases diagnosed each year (30% of them fatal). GSK received regulatory approval for Cervarix in China in July 2016, and the company has partnered with China’s e-commerce company Alibaba, which now allows patients to schedule Cervarix vaccination appointments at a network of 1,500 local healthcare centers, according to GSK.
Merck nominally has an upper hand in the market, in that its original vaccine was effective against four virus types, and the newer Gardisil 9 protects against nine types; GSK is reportedly selling Cervarix at a 40% lower price, and garnered an earlier approval in the Chinese market. But GSK and Merck domination on Chinese soil may ultimately be short-lived, as three Chinese companies — Walvax Biotechnology Co. Ltd., Xiamen Innovax Biotech Co. Ltd. and Zhejiang Pukang Biotechnology Co. also have their own HPV vaccines in clinical trials. Analysts predict that the ultimate availability of HPV vaccines from local companies will likely curtail sales for Gardasil and Cervarix over time.
With regard to addressing healthcare inequity related to cervical cancer prevention worldwide, the Gavi Alliance has, since 2016, provided HPV vaccination to more than one million females/year in over 23 developing nations, using both Cervarix and Gardasil, which are being supplied at reduced cost by GSK and Merck. Gavi’s goal is to immunize 40 million girls with HPV vaccines by 2020, to avert an estimated 900,000 deaths.
Case #4 — Two big setbacks in dengue fever. Mosquito-borne dengue fever is the world’s fastest-growing infectious disease, and the leading cause of death among children in some parts of Asia and Latin America, according to WHO. In the past half century, dengue has spread 30-fold, from fewer than 10 to 128 countries (potentially exposing 4 billion people). Globally, this painful bone and joint disease — for which there is no known treatment, and which individuals can get many times in their lifetime — is estimated to cost $9 billion/year in direct medical costs and indirect costs, and is to blame for an estimated 20,000 deaths/year.
Sanofi Pasteur invested $1.7 billion over 20 years to develop its Dengvaxia vaccine to prevent dengue fever. Approved in April 2016, the first-in-class vaccine for dengue is now licensed for use in more than 19 dengue-endemic countries. Dengvaxia has been shown to prevent 93% of severe disease and 80% of hospitalizations due to dengue, according to large-scale clinical studies conducted in 10 countries in Latin America and Asia. However, the road for Dengvaxia has been anything but smooth.
In November 2017, Sanofi Pasteur announced that, for recipients who had never had dengue fever (so-called dengue-naïve patients), the vaccine can make future dengue episodes more severe; thus the labeling on Dengvaxia has been revised to limit the vaccine’s use to only those patients who have already had dengue fever, and that the vaccine should not be given to dengue-naïve individuals.
Another setback for Dengvaxia unfolded in late 2017, when 14 children in the Philippines died during a vaccination campaign involving 800,000 children, prompting the Philippine government to suspend its Dengvaxia vaccination campaign. Health authorities in the Philippines have cited “causal association” in three of the child-death cases, but say further testing is needed.  In January 2018, Sanofi Pasteur agreed to refund the Philippine Government $28 million for unused Dengvaxia doses and to pay for Dengvaxia adverse events that are scientifically proven to be caused by the vaccine. Since then, the country’s health authority also asked the company for a full refund for the $70-million program. The company has refused, saying doing so would imply that the vaccine does not work. 
“An alternative approach that is being considered by many is to support and license technologies that are developed and can be manufactured for considerably lower cost in those regions,” says Mohan of IQVIA.
GSK, Merck Sharpe & Dohme, and Takeda Pharmaceuticals are also working on dengue vaccines for all people, not just those who have already been infected by the virus. Thanks to prevalence of dengue in at least 128 countries (exacerbated in part by population density and global warming), the global dengue vaccines market is projected to grow at a CAGR of 15% from 2017–2021, according to a November 2017 report by market research firm TechNavio. 
Targeting nosocomial (hospital-acquired) infections
The overprescribing of antibiotics, combined with poor hygiene and infection control within hospitals, nursing homes and long-term care facilities has made the scourge of nosocomial (hospital-acquired) infections — from methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. diff.) and other bacterial pathogens — a major public health issue today. According to CDC, in the US alone, nearly 100,000 patients die each year as a result hospital-acquired infections, which generate an estimated $20 billion in additional healthcare costs, and these virulent infections become harder to treat over time.
The most common nosocomial infection, C. diff., causes severe, antibiotic-resistant diarrhea. In the US alone, there are nearly 500,000 cases of C. diff. infection each year, creating $4.8 billion in excess healthcare costs, according to CDC. And importantly, nearly 30,000 Americans die each year from their C. diff. infection within one month of initial diagnosis. Recurrence occurs in roughly 20–25% of people who have had the infection. Patients who develop one recurrent episode have up to a 35% chance of having another one, and patients with at least three episodes have up to a 65% chance of additional recurrences.
When it comes to C. diff. infection, it’s not the bacteria that does the damage, but the toxins (called Toxins A and B) it produces in the body; as such, the so-called use of a “toxoid vaccine” methodology has proven to be the winning ticket; once Toxin A and/or and/or Toxin B are inactivated and can be injected into the body in vaccine form, they produce the desired immune response.
Merck’s Zinplava (bezlotoxumab) was the first C. diff. vaccine to receive FDA approval (in October 2016). It is a fully human monoclonal antibody (MAB) that binds to and neutralizes Toxin B; however, Zinplava does not prevent C. diff. infection, rather it reduces the its recurrence. Early projections for of Zinplava were for sales of $250 million/year, and the success of the methodology drew others into the fray.
Until recently, three other companies — Sanofi Pasteur, French biotech company Valneva SE and Pfizer — were in hot pursuit to pioneer C. diff. vaccines that would not only reduce recurrence, but would protect against C. diff. infections altogether. However, recent setbacks have winnowed the field.
Valneva’s prophylactic candidate vaccine against C. diff. infection (VLA84) passed a Phase II study last year, and is said to use a contrasting method of action that could provide some clinical advantage. But without sufficient funding to carry out Phase III trials, the company has put the program on hold for the moment.
Meanwhile, citing “low probability” of meeting its primary clinical objectives, Sanofi Pasteur announced last December that it was suspending its investigational C. diff. toxoid vaccine program (PF-06425090) “to focus on six key vaccine projects currently in development.”
This leaves Pfizer’s investigational PF-06425090 vaccine for C. diff. infection — which was fast-tracked by FDA in August 2014 — first in line. Its Phase III trials, initiated in March 2017 involving roughly 16,000 participants, are expected to be completed in September 2020.
The C. diff. vaccine space in the US, Europe and Japan is projected to grow from $630 million in 2016 to $1.7 billion by 2026 (a 10.2% CAGR), according to a July 2017 report by market research firm Global Data. However, total market size will ultimately depend on whether the C. diff. vaccine is largely used on an ad hoc basis with at-risk patients, or whether its use is ultimately recommended as a prophylactic measure for all at-risk patients in institutional settings.
Cambridge, MA-based biotech Affinivax is also working with Nosocomial Vaccine Corp. (NVC; which was established by ClearPath Development Co. and Astellas Pharma) to pursue a range of vaccines targeting hospital-acquired bacterial infections using Affinivax’s proprietary vaccine platform, Multiple Antigen Presentation System (MAPS).
Seasonal flu’s effectiveness gap
Seasonal flu places an enormous substantial burden on healthcare systems each year. CDC estimates that in the US influenza has resulted in between 9.2 million and 35.6 million illnesses, between 140,000 and 710,000 hospitalizations, and between 12,000 and 56,000 deaths annually since 2010. WHO estimates that influenza kills between 250,000 and 500,000 people around the world every year.
The challenge with developing a seasonal flu vaccine is that in any given year, there are many different flu viruses circulating and some are constantly mutating. The need to re-formulate and manufacture a new flu vaccine each year, and re-administer the new vaccine each year in mass vaccination campaigns, is enormous costly, and is not always successful. According to the CDC, over the past 13 years, the “vaccine effectiveness” of the annual flu vaccine approved each year has ranged from a high of 60% to just 10% in any given year. 
The 2017–2018 flu season in the US is shaping up to be one of the worst in recent history, thanks in part to a particularly deadly strain called influenza A (H3N2). This year’s flu vaccine is estimated to be only 36% effective, according to CDC. “When efficacy rates for the shot turn out to be so low, a self-defeating cycle ensues, raising questions and skepticism among the populace and further reducing voluntary vaccination rates, which then allows for more flu infections and depressed herd immunity that is so essential to slowing the spread of the seasonal flu,” explains Nitin Mohan, Vaccines Therapy Area Lead for IQVIA.
All of this cost and variability continues to put wind in the sails of the idea of developing a “universal flu vaccine” — one that can provide broader, more durable protection against many strains of influenza, with immunity sustained over time. Today, a variety of public-private stakeholders are developing a universal flu vaccine, among them:
• Vaccitech Ltd. (a spinoff of the University of Oxford) moved its patented candidate MVA-NP+M1 into its first two-year, 2,000-patient clinical trials in late 2017. The vaccine formulation uses more-consistent proteins in the virus’ core, rather than less-stable surface proteins that can change and mutate easily. This produces a universal vaccine against many different influenza viruses, and stimulate the patient’s immune systems to boost T-cells, rather than just producing antibodies to combat the virus, according to the company.
• Biotechnology company FluGen is using a different approach, using vaccine viruses with a gene deletion. The company’s candidate, dubbed RedeeFlu, has received $14.4 million funding from the US Dept. of Defense, to support placebo-controlled clinical trials.
• The non-profit, public-private consortium called the Human Vaccines Project launched the Universal Influenza Vaccine Initiative (UIVI) in October 2017. The consortium — which includes biopharma companies GSK, MedImmune, Illumina, Sanofi Pasteur, Johnson & Johnson/Janssen, Pfizer, Moderna, Boehringer Ingelheim, Aeras, as well as university and government researchers — is pursuing a vaccine that is focused on the more-stable stalk region of the hemagglutinin (HA) protein of the influenza virus. With a series of clinical trials set for 2018, the group plans to analyze blood and tissue samples from vaccinated and infected individuals, and use artificial intelligence (AI) and simulation models to understand why some people are protected while others are not.
• Sanofi Pasteur, the world’s largest flu vaccine manufacturer has partnered with Boston-based biotech, Berg, to harness that company’s algorithm- and probability-based AI capabilities, to identify specific biomarkers that could improve the specificity of future flu vaccines. Sanofi is running a longitudinal study on its licensed flu vaccines, and Berg will analyze the molecular and clinical data from individuals participating using using its proprietary Interrogative Biology Platform and “bAIcis” AI tool.
Modeling & simulation
The use of so-called model-informed drug development (MIDD) is on the rise among some biopharma manufacturers. This approach uses preclinical and clinical trial data related to safety and efficacy to build and verify models that can be used to simulate and predict the pharmacodynamic response to the vaccine in larger patient populations, and within specific simulated patient cohorts. Similarly, ongoing advances in modeling, simulation and AI are helping drug developers to leverage large, complex data sets in search of previously unrecognized patterns, trends and insights.
“Until now, we have lacked the biomedical and computational tools to probe the complex and dynamic features of the human immune system in a complete way,” says Dr. James Crowe Jr., Director, Vanderbilt Vaccine Center, who is leading the Universal Flu Vaccine Initiative. “But with today’s technology, we can decipher the core principles behind how the immune system protects vulnerable populations, and develop a full understanding of how it prevents and controls influenza to inform the development of a universally effective vaccine.”
“We’ve seen a growing number of biopharma drug developers embracing MIDD concepts as they develop a vaccine candidate. Pharmacodynamic response to vaccines can be analyzed in the same way we look at response to traditional drugs, allowing us to evaluate candidate molecules more quickly, inform ongoing clinical trial work and simulate response in simulated patient populations, and to support dose formulation and schedule selection,” says Michael Dodds, PhD, executive director, Certara Strategic Consulting. “However, within the realm of vaccine development, developers have not yet embraced it as fully as they should, and this signals an enormous missed opportunity.”
The Bill and Melinda Gates Foundation has been working to reduce infant mortality in infants in low- and middle-income countries by providing large-scale flu and Tdap (for diphtheria-tetanus-pertussis prevention) vaccination campaigns for pregnant women. Recently, the Gates Foundation carried out a modeling study, working with Certara, to identify the most optimal time to vaccinate pregnant women in order to confer the highest-possible level of antibodies to the newborn at birth. As newborn babies cannot be vaccinated against infectious diseases for at many months, their only opportunity for lifesaving immunity comes from the antibodies they receive from their mothers at birth.
“We used the Gates Foundation data from these vaccination efforts —involving different vaccines, in three separate global studies, involving thousands of mother-newborn pairs — to identify the optimal time for vaccinating Mom,” explains Dodds of Certara. “Using modeling, we were able to infer a kinetic profile of antibody generation as a function of time across the global population, and this insight helps to identify the optimal time to vaccinate women during pregnancy, in order to confer the most robust protection for infants in the first six months of life.” The results were presented at ASCPT 2017. 
Clinical trial design and enrollment also present their own challenges, but these can become particularly challenging in developing nations, for drugs involving pediatric patients, says Nathalie Sohier, MD, MPH, global head of infectious disease and vaccines therapeutic area for Parexel. Having worked on more than 30 vaccines (including dengue, malaria, pneumococcal diseases, influenza, norovirus and respiratory syncytial virus [RSV]) over the past 5 years, the company has developed a variety of data-driven strategies and best practices related to the clinical trial design, recruitment, enrollment and retention. “Manufacturers cannot control where epidemics (like flu or RSV) will strike, so it can be hard to organize vaccine trials in advance, so we help biopharma companies open more testing sites in advance to make sure they have the cases when they need them.”
Meanwhile, clinical trials related to pediatric vaccines “can have particularly complex requirements, in terms of special training that is needed for medical professionals to work with children, and the need to inform parents with culturally sensitive educational materials. Acceptance or antipathy toward pediatric vaccines is unique to every country and every culture and the local history with vaccinations,” adds Francine Oko, senior solutions consultant, infectious diseases, for Parexel. “Developing and sharing educational materials aimed at public education early in the process can help to build confidence in the science, which helps to maximize marketed vaccine uptake over time.”
Changing the manufacturing paradigm
“Vaccines are among the most complicated biopharmaceutical products and the cost to manufacture them varies considerably (ranging from pennies to thousands of dollars per vaccine). At the same time, pricing negotiations are often completed by the need to negotiate with centralized buyers, which may be governments or NGOs such as WHO, UNICEF or the Gates Foundation,” says Ranjeet Patil, segment head, vaccines and viral therapies for MilliporeSigma, the life science business of Merck KGaA (Darmstadt, Germany).
In most vaccine-manufacturing routes — whether using live (attenuated) or dead (inactivated) organisms (bacterial and viral pathogens), conjugate vaccines, toxoid vaccines, recombinant vaccines and more) —purification, separation, formulation and sterilization of the target antigen are said to account for up to 80% of the manufacturing costs. And manufacturing and distribution challenges associated in developing nations are further compounded by structural issues ranging from non-existent or insufficient manufacturing and supply-chain infrastructure, inadequate cold-chain transportation and storage capabilities, inability to stockpile supplies due to short expiry dates, erratic power-grid reliability and more.
At the same time, Patil of MilliporeSigma notes that there has been a trend away from large, centralized manufacturing facilities in North America, Europe and toward smaller-scale, decentralized and localized production facilities. Mohan of IQVIA adds that in recent years, India, Brazil and China have developed robust vaccine R&D, manufacturing infrastructures and a growing legion of both trained healthcare workers needed to assist in mass-vaccination campaigns, but says most other developing nations do not yet have sufficient infrastructure for vaccine manufacturing and dissemination.
“Ultimately, the goal is to expand access to lifesaving vaccines by validating simplified manufacturing processes that are more amenable to technology transfer, faster deployment, assembly and qualification,” says Patil. “This lets developing nations build manufacturing capacity and self-sufficiency, and reduce the dependence on cold-chain storage and distribution networks in favor of local production capabilities.”
To that end, MilliporeSigma acquired Ontario-based Natrix Separations last September, to leverage Natrix’s products and proprietary, single-use, rapid-cycling chromatography technology platform. “Normally the downstream purification process is complex, costly and hard to transfer; by comparison, this technology can be transported and deployed quickly without much operator training, and provides high productivity and improved impurity removal, making it an ideal fit for bioprocessing operations, and enabling faster, more-efficient drug and vaccine development,” explains Patil. “We’re seeing more and more of the big, established vaccine makers adopting single-use and flexible manufacturing techniques. The lessons learned create a real opportunity for emerging nations to literally leapfrog past their existing lack of infrastructure and build better, advanced capabilities today, without being locked into the old conceptual mindset that says ‘this is the way it’s always been done.’”
To further advance such manufacturing advances for vaccine manufacturers, Merck KGaA is also part of the DiViNe Project (a consortium of six European companies), which is working to improve affinity chromatography (one of the key purification processes required during vaccines manufacturing) and develop an integrated purification platform to capture antibodies more cost-effectively. MilliporeSigma has also partnered with South Korea’s International Vaccine Institute (IVI), to improve yield and recovery and streamline complex vaccine-manufacturing processes involving conjugated polysaccharide vaccines (discussed in detail below), and has been working with a number of leading biopharmaceutical companies, to develop vaccines and viable production routes for Ebola and other tropical infectious diseases.
Three advancing areas in vaccine development:
Conjugated polysaccharide protein vaccines. In recent years, there has been growing interest in the pursuit of next-generation processes for clarification and purification to ensure high-quality, affordable vaccines based on bacterial (not viral) pathogens. This newer vaccine methodology involves conjugating the polysaccharide portion of the bacteria (generally from the surface) with protein carriers; this combination helps to produce stronger immune response against the targeted bacterial pathogens.
mRNA vaccines. Considerable effort is underway to develop vaccines based on the co-called “messenger RNA” or mRNA platform. The idea is to use the genetic material mRNA to encode antigens that will produce improved immunization response compared to present cell-based, inactivated or purified antigen, or toxoid vaccines, and enable the use of agile and flexible manufacturing methodologies. Specifically, this opens the door for rapid, large-scale production at the point-of-care, enabling more-rapid response to infectious disease outbreaks. In addition, mRNA vaccines are said to be more stable over wider temperature range for longer periods of time, expanding the potential to use them in tropical and sub-tropical regions where cold-storage capabilities are lacking. In recent years, companies pursuing mRNA technologies have attracted more than $3.4 billion from equity investments and partnership payments, according to one study. 
Today, there are at least 12 vaccines based on mRNA technology under development. Biopharma companies CureVac AG, Moderna, BioNTech, eTheRNA, RaNA Therapeutics, Neon Therapeutics and others are actively pursuing mRNA-based vaccines, against Zika, rabies, respiratory syncytial virus (RSV), rotavirus infections, as well as other bacterial and viral infections and certain cancers. And these efforts have been attracting attention and financing from many Big Pharma players. For instance:
* In October 2017, Eli Lilly established a $1.8 billion deal with CureVac AG to develop five mRNA cancer vaccines that will use the company’s proprietary RNActive technology to deliver mRNA that ultimately directs the immune system to target the encoded neoantigens. The company is also in the early stages of developing prophylactic mRNA vaccines for influenza, HIV and respiratory syncytial virus (RSV)
* Roche’s Genentech has an mRNA deal with BioNtech, in a deal reportedly worth $310 million up front, to pursue a skin cancer therapy
* Moderna Therapeutics has launched Phase I trial for mRNA-4157, an mRNA-based personalized cancer vaccine, with $200 million in funding from Merck. Moderna is also pursuing a vaccine against Zika and flu, and a therapy for heart failure. In March 2013, a few months after Moderna announced itself to the world, AstraZeneca put an up-front $240 million into a partnership to pursue up to 40 drug candidates using Moderna’s mRNA technology and proprietary, lipid-nanoparticle-based delivery systems and non-lipid formulations that may limit toxicity.
Viral-vector platforms and virus-like particles (VLPs). Viruses are able to enter inside cells of other organisms and deliver their genetic material. Exploiting this property, vaccine makers have developed recombinant viral vectors — particles derived from viruses that have been engineered to lose their pathogenicity but still deliver their chosen genetic material into cells to produce the desired immune response. Today, viral vector vaccines have already been used extensively in veterinary medicine, and this approach is being used in the pursuit of prophylactic and therapeutic vaccines in complex disease such as HIV, malaria, measles and others, and in cancer immunotherapy.
Viral vectors are particularly useful in enabling vaccines to carry multiple antigens from different strains of the same pathogen, or protective antigens from two or more disease pathogens. As such, their use opens the door for improved immunization against one disease, or the ability to use a single vaccine against several diseases. Pfizer, Sanofi Pasteur, Biogen, Shire, Theravectys (a spinoff of the Pasteur Institute), Sirion Biotech, Cologne-based Cevec Pharmaceuticals GmbH, Jannsen Vaccines & Prevention B.V., and others are working in this realm.
“Viral vector platforms can allow vaccine developers to produce vaccines for different diseases by leveraging the same manufacturing processes,” explains Patil of MilliporeSigma. “This opens the door for a template-driven manufacturing platform that is more scaleable than that required conventional vaccine-manufacturing processes.”
Similarly, virus-like particles (VLPs) are biological nanoparticles that are engineered to mimic the overall structure of a virus but without the infectious genetic material or the ability to replicate. Thus they can be engineered and used to trigger a desired immune response, and offer a safer alternative than vaccines based on live viruses. Some VLP-based vaccines are already on the market for infectious disease — specifically for hepatitis B (from Merck, Sanofi Pasteur and GSK) and HPV (from both Merck and GSK), and others are in clinical development (for hepatitis C, Zika virus, RSV, Ebola, malaria and others). Novamax, Medicago, Takeda, Cytos Biotechnology, Xiamen Innovax Biotech and others are working in this area.
1. Morbidity and Mortality Weekly Report, 63(16);352-355; April 2014; https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6316a4.htm
2. International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health. Vaccines Work: Key Facts and Figures. Retrieved at http://wwwjhsph.edu/research/centers-and-insti- tutes/ivac/resources/vaccine-cost-e ectiveness.html
3. Nature Reviews Drug Discovery 1, 373 (2015); doi:10.1038/nrd4660
4. Bouza E., Consequences of Clostridium difficile infection: Understanding the healthcare burden. Clin Microbiol Infect 2012; 18(Suppl 6): 5–12.
7. As reported by Reuters on February 2, 2018: https://www.reuters.com/article/us-sanofi-dengue-philippines/philippines-says-anti-dengue-vaccine-may-be-connected-to-three-deaths-idUSKBN1FM0SP)
11. American Society for Clinical Pharmacology and Therapeutics (ASCPT), Clin. Pharmacol. Ther., 2017, 101: S5–S99. doi:10.1002/cpt.570; https://www.ascpt.org/Portals/28/docs/Annual%20Meetings/Annual%20Meeting%20Archive/2017%20ASCPT%20Annual%20Meeting%20Program%20for%20website.pdf?ver=2018-01-19-101524-573
12. mRNA Vaccines & Therapeutics: Are you ready to be on the ground floor of the next therapeutic modality, 23 June 2017, pipelinereview.com; http://pipelinereview.com/index.php/2017062365045/DNA-RNA-and-Cells/mRNA-Vaccines-Therapeutics-are-you-ready-to-be-on-the-ground-floor-of-the-next-big-new-therapeutic-modality.html