The words respiratory syncytial virus (RSV) can strike fear into the hearts of parents of infants and young children. However, RSV also attacks older adults, particularly if they suffer from preexisting conditions. Indeed, RSV imposes a significant disease burden on older adults. It is estimated that in 2019, RSV caused 5.2 million cases of acute respiratory infection, 470,000 hospitalizations, and 33,000 in-hospital deaths in adults 60 years of age and older in industrialized countries (Savic et al. Influenza Other Respir. Viruses 2023; 17(1): e13031).

These figures highlight the need for RSV prophylaxis—a need that has been hard to meet, given the lack of approved RSV vaccines. Fortunately, progress toward RSV vaccines has been reported by several developers. For example, at last month’s World Vaccine Congress, scientists from several companies discussed how RSV vaccines are “around the corner.” These companies—Pfizer, GlaxoSmithKline (GSK), Moderna, and Merck & Co.—are contributing to RSV vaccine technology in various ways, as this article relates.

Groundbreaking studies

More than half a century ago, the development of RSV vaccines began with disastrous consequences. “In the late 1960s, infants and toddlers were given an RSV vaccine, but when they were subsequently exposed to RSV, they got sicker—and two children died,” reflects Alejandra Gurtman, MD, vice president, vaccine clinical research and development, Pfizer. The RSV vaccine’s failure was initially attributed to formalin, which was used to inactivate the virus. Specifically, formalin was thought to disrupt protective antigens.

Subsequent research, however, revealed that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Also, it was determined that the formalin-inactivated RSV vaccine generated a pathogenic Th2 memory response that led to a significant increase in severity and frequency of RSV infections.

As Gurtman points out, from the 1960s to 2013, many different vaccine platforms were tried, but without success. Nonetheless, the field slowly progressed, and so did its instrumentation. “Advances in science, such as crystallography, paved the way for studies that determined the RSV virus’s fusion protein (F) exists in two different conformations,” she details. “One is an unstable prefusion form attached to the viral envelope and called RSVpreF. Because it could elicit a strong immune response, preF became a key vaccine target.

“Pfizer took the structure of this protein, stabilized it, and made it into a bivalent subunit vaccine. We have shown that this stabilized preF protein is very stable and generates high levels of antivirus antibodies. In 2018, the first human studies began. And now, in 2023, we have validation that the vaccine is 85.7% efficacious in individuals 60 and older. Further, it is well tolerated, and when we look at other side effects such as fever, headache, or fatigue, we see no difference between vaccine and placebo groups.”

The FDA, which earlier gave the company a breakthrough therapy designation for this vaccine, is expected to announce a decision by the end of May. “We would have supply available immediately to vaccinate older adults,” Gurtman remarks. “Fortunately, for the tripledemic challenge next year, we hope to provide this vaccine to protect older people from RSV.”

The company is also closing in on approval of its maternal RSV vaccine indication. “We’ve done groundbreaking work for developing an RSV vaccine for pregnant mothers 24–36 weeks of gestation,” Gurtman asserts. “With RSVpreF, vaccinated mothers develop a high level of antibodies that is passed along to the baby.

“We have shown the vaccine is 82% efficacious in protecting babies against severe disease in the first six months of life, when infants are most at risk for serious illness. We believe this is going to be a very important step in protecting many infant lives from RSV.” Pfizer also is continuing to develop and test RSVpreF for use as a vaccine in individuals of other ages.

Adjuvant systems

Sometimes adding adjuvants to vaccines can help generate a stronger immune response. As a diverse group of immune-modulating agents, adjuvants can be found in vaccines such as for diphtheria, polio, tetanus, pneumonia, and hepatitis.

GlaxoSmithKline (GSK) has devoted several decades to developing a portfolio of adjuvant systems. Its liposome-based vaccine adjuvant called AS01E is included in the company’s RSV vaccines for older adults.

Piyali Mukherjee
Piyali Mukherjee, MBBS

“Older individuals (60-plus years) are at high risk of severe illness due to RSV, and those with underlying comorbid conditions are even at greater risk,” says Piyali Mukherjee, MBBS, vice president and head of global affairs, vaccines, GSK. “Our RSV older adult vaccine candidate contains a purified recombinant prefusion RSV F antigen (RSVPreF3) combined with our proprietary AS01E adjuvant. It is designed to deliver high vaccine efficiency in groups of people who need protection against natural RSV disease and who are at high risk for severe complications due to RSV, given the natural age-related decline in the immune system observed in older adults.”

The company reports that across multiple studies, the vaccine demonstrated a favorable safety profile with no imbalance in the overall incidence of serious adverse events, fatal adverse events, or potential immune-mediated diseases.

Mukherjee reports, “We are confident we have a potential best-in-class vaccine profile with 82.6% overall vaccine efficacy and over 94% efficacy observed against RSV lower respiratory tract disease in adults with at least one comorbidity of interest (the population that drives most RSV hospitalizations) and against severe disease. We believe our data are clinically meaningful and relevant to healthcare professionals.

“We are on track to deliver potentially one of the first RSV older adult vaccines in 2023, pending regulatory approval. We hope to have a decision from the FDA by May 3, 2023, and to launch as quickly as possible afterwards. Our RSV older adult vaccine candidate is also under regulatory review by the European Medicines Agency; Japan’s Ministry of Health; Labor and Welfare; and several other regulators, with decisions expected in 2023.”

GSK is conducting three additional Phase III trials that aim to expand the RSV vaccination for adults aged 50–59 years. “Adults with comorbidities in this age range are at an increased risk of developing severe RSV, with many people aged 50 and above having at least one comorbidity,” Mukherjee notes.

For the future, GSK is also investing significantly in coadministration studies with influenza vaccine. “This will help implement our RSV vaccine in older adults,” Mukherjee predicts. “Given the challenges in pharmacies and physician’s offices during influenza season, we believe showing that our RSV vaccine can be coadministered with the most commonly used types of influenza vaccines is important.”

GlaxoSmithKline is developing an RSV vaccine
GlaxoSmithKline is developing an RSV vaccine candidate for older adults (RSVPreF3 OA). In addition to a purified recombinant prefusion RSV F (RSVPreF3) antigen, the vaccine candidate incorporates a proprietary adjuvant system (AS01E). This system contains an adjuvant (QS-21 Stimulon) licensed from Antigenics. In a Phase III trial, RSVPreF3 OA was shown to be highly efficacious, demonstrating an overall vaccine efficacy of 82.6% against RSV lower respiratory tract disease.

An mRNA vaccine

Already notable for developing mRNA therapeutics and for introducing a breakthrough vaccine against COVID-19, Moderna now has RSV in its sights. “Our success with COVID-19 enabled us to attract a tremendous pool of talent and expertise which has enabled rapid RSV development,” says David Martin, MD, MPH, vice president, global head of medical RWE, Moderna. “Furthermore, regulators and other health authorities around the globe are familiar with the mRNA platform technology.

David Martin
David Martin, MD, MPH

“We designed and screened many mRNA sequences encoding RSV-prefusion F, covering both protein and nucleotide sequence optimization, and selected the one that showed the highest expression and immunogenicity in preclinical models. The prefusion F protein targeted by our RSV vaccine is highly conserved, and we do not anticipate that we will need to change the vaccine each year.”

Moderna’s candidate, mRNA-1345, consists of a single mRNA sequence encoding for a stabilized prefusion F glycoprotein complex and employs the same lipid nanoparticles used in its COVID-19 vaccines.

Moderna reports that its recent ConquerRSV Phase III pivotal efficacy trial demonstrated a vaccine efficiency of 83.7% against RSV-lower respiratory tract disease (defined in older adults by two or more symptoms). The company also indicates that mRNA-1345 was well tolerated and that no safety concerns were identified. Safety and tolerability will continue to be followed as the study continues.

“In our large Phase III trial with participants from over 20 countries, we demonstrated vaccine efficacy in a diverse population exceeding 35,000 that included individuals with comorbidities including chronic obstructive pulmonary disease and congestive heart failure,” Martin declares. “Subject to regulatory authorization, we hope to distribute our RSV vaccine starting in 2024.”

Moderna is using its breakthrough mRNA platform
Moderna is using its breakthrough mRNA platform technology to develop an RSV vaccine candidate. Called mRNA-1345, the vaccine candidate incorporates a single RSV mRNA sequence encoding a stabilized prefusion F glycoprotein. The sequence is encapsulated by and delivered via the same lipid nanoparticles used in Moderna’s COVID-19 vaccine. Phase III trials demonstrated that mRNA-1345 has an efficacy of 83.7% in older adults. [Bearwalk Cinema]

Passive vaccination

“Vaccines have provided incredible public health benefits against many different infectious diseases. [This success is due to] traditional vaccines, which  represent active measures that induce the host to make antibodies against the disease being targeted,” points out Kevin Russell, MD, MTMH, section head, pediatric portfolio, global clinical research, Merck Research Laboratories. “However, in the case of RSV, the challenge for newborns or premature babies is that they don’t have an adequate or mature enough immune system to respond well to traditional active vaccinations. That’s where passive vaccination with monoclonal antibodies (mAbs) can play a role.

Kevin Russell
Kevin Russell, MD, MTMH

“The advantage of passive vaccination is that its onset is immediate. You don’t have to wait for the immune system to create the antibodies for protection. It also provides very specific protection since mAbs can be designed only to attack and neutralize the infectious agent—in this case, RSV.”

Russell notes that in the 1990s, the first anti-RSV mAb (palivizumab) was developed to reduce infection in high-risk infants. Palivizumab proved that mAbs could have an impact on RSV. Coupled with advances in structural biology and with this new knowledge, vaccines began advancing on many fronts, including development of a new generation of mAbs that can limit infections.

Merck & Co. is developing a fully human, half-life-extended, RSV-neutralizing mAb (MK-1654—clesrovimab). “One advantage our product has over those in development or currently available is that only one vaccination is needed for the entire RSV season, since it was designed to have an extended half-life that would last five to six months,” Russell points out. “Thus, monthly administration is not needed.

“We feel that clesrovimab has the ability to evade RSV alterations since it targets a highly conserved site of the F protein. Clesrovimab is being studied in full-term healthy infants in addition to high-risk infants. The absolute burden of RSV is highest in healthy infants, making it an unmet medical need that we would like to meet.”

The company expects data from its Phase III trials to be available in the second half of 2024.

Russell proposes that mAbs such as those from Merck & Co. could play a large role in reducing the RSV burden globally: “One of the things that is important when considering vaccination of all infants with clesrovimab is that it is treated as a vaccine. This will help ensure there is meaningful uptake in countries around the world.

“However, in many countries, mAbs are not treated as vaccines. In order to have the uptake needed to effect changes in morbidity and mortality, global policy changes may be needed, allowing implementation through national immunization programs.”

“We have seen phenomenal and amazing progress with promising vaccines (active or passive) in the last couple of years—and even within the last month,” Russell declares. “The time is upon us that we will finally have mitigations against RSV.”

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