Viruses, Variants and Vaccines: Staying Ahead of the Spread

In the wake of the COVID-19 pandemic, the critical role of vaccines in stopping the spread of infectious diseases has become undeniable. The global response to the pandemic underscores the urgent need for effective vaccines to combat emerging threats and safeguard public health. Despite the challenges the world experienced during the pandemic, researchers worldwide continue to pioneer breakthroughs in vaccine development. From the Zika virus to Lyme disease, ongoing efforts offer promise for the creation of new vaccines.

Before looking at some of the new breakthroughs, here’s a summary of historic successes of vaccines in the past. 

Vaccine Successes

• Smallpox. Smallpox was “one of the most devastating diseases known to humanity,” according to the World Health Organization (WHO), as it caused millions of deaths over the course of 3,000 years before it was eradicated. Edward Jenner, MD, first developed a vaccine for smallpox in 1796. WHO launched an intensified plan to eradicate the virus in 1967. By 1977, the last known natural cause was in Somalia. In 1980, WHO declared the disease eradicated.¹

• Polio. Polio has been in existence for thousands of years. In 1988, the World Health Assembly adopted a resolution for the worldwide eradication of polio. Jonas Salk, MD, is credited with developing the first successful inactivated polio vaccine (IPV), which was announced in 1955. In the 1960s, Albert Sabin, MD, developed the oral polio vaccine (OPV). One estimate says the use of polio vaccines prevented five million cases of paralytic polio between 1960 and 1987 and 24 million cases worldwide between 1988 and 2021, compared to a counterfactual world with no polio vaccines.² Just two endemic countries remain: Pakistan and Afghanistan.³ As such, the world remains at risk, especially those with weak public health and immunization services or whose travel or trade links remain open to endemic countries. 

• Measles. Measles can spread quickly and can even be fatal in children. WHO reports that before the introduction of the measles vaccine in 1963 and widespread vaccination, major epidemics occurred approximately every two to three years and caused an estimated 2.6 million deaths each year.⁴ John Franklin Enders, PhD, a biomedical scientist, developed a measles vaccine along with his team. By 1961, it was considered 100 percent effective and was licensed for public use in 1963. In 2000, measles was declared eliminated (meaning the absence of continuous transmission for more than 12 months) in the United States, largely due to widespread vaccination efforts. With accelerated immunization activities by countries, WHO, the Measles & Rubella Partnership (formerly the Measles & Rubella Initiative) and other international partners, 56 million deaths were successfully prevented between 2000 and 2021.⁴

• Diphtheria. Diphtheria was a leading cause of childhood death in the pre-vaccine era.⁵ It is fatal in five to 10 percent of cases with a higher mortality rate among young children. Diphtheria was described by Hippocrates in 5th century B.C. prior to epidemics in the 6th century. The diphtheria-tetanus-pertussis (DTP) vaccine was introduced after World War II, resulting in a decreased incidence of the disease in industrialized countries. It should be noted that the decrease in diphtheria morbidity and mortality rates in the United States after 1925 might, in part, be attributed at least to artificial immunization.⁶ But that does seem improbable based on the number of people who were immunized. Cases did gradually decline after vaccines were introduced in the 1940s, then rapidly declined after a universal vaccination program. From 2002 to 2022, only six cases were reported in the United States.⁷

Most reported tetanus cases are birth-associated among newborn babies and mothers who have not been sufficiently vaccinated with a tetanus-toxoid-containing vaccine (TTCV). In 2018, approximately 25,000 newborns died from neonatal tetanus, which was a 97 percent reduction from 1988 when an estimated 787,000 newborn babies died within their first month of life.⁸ The TTCV vaccine was developed by multiple researchers over several decades. Gaston Ramon, MD, was one of the earliest researchers to develop the TTCV vaccine in the 1920s. Other vaccines are also used to treat tetanus, including Td, Tdap and DTaP. While tetanus is preventable through the administration of vaccines, the disease is not eradicated due to a high prevalence of bacteria in the environment. 

Staying Ahead of the Spread

Conventional vaccines use one or several antigens derived from inactivated or weakened pathogens, or their components such as protein subunits or toxins, to generate an immune response.⁹ These vaccines are time-consuming to produce, involve a greater risk of reversion to virulence, and need more customized development against emerging or rapidly evolving pathogens. 

Looking ahead, newer epidemiological surveillance tools are being used for the challenges of new and existing viruses and diseases. Those tools include artificial intelligence and wastewater surveillance; the evolution of rapid, multiplex and easy-to-use diagnostics; and the prompt development and evaluation of novel therapeutics.¹⁰ 

As of Jan. 1, 2023, the global vaccine research and development landscape included 966 candidates, among which 23 percent (220) were traditional inactivated or attenuated vaccines. Advances in molecular technologies have led to the development of other platforms.¹¹ Following is a look at some of the studies being performed on various vaccines to stay ahead of the spread. 

Recombinant Protein Vaccines

Recombinant vaccines can treat hepatitis B virus, human papillomavirus (HPV), pertussis (whooping cough), influenza, COVID-19 (SARS-CoV-2), malaria, Lyme disease and others. Nearly 100 recombinant vaccine candidates are in Phase I development, making it the highest number at this stage among all platforms.¹¹

Lyme disease cases have doubled since 2000 to nearly 500,000 per year in the United States. Pfizer anticipates U.S. Food and Drug Administration (FDA) approval in 2026 for the VLA15 vaccine, which is in clinical trials. The vaccine works by targeting an outer surface protein of Borrelia burgdorferi — the bacterium that causes Lyme disease. The vaccine blocks the protein OspA, which prevents the spiral-shaped bacterium from being able to leave the tick and infect humans it has bitten.¹²

Two recombinant protein vaccines, PF-06928316 (Pfizer’s ABRYSVO) and GSK3844766A (GSK’s AREXVY), have resulted in a greater than 80 percent protection in Phase III trials for respiratory syncytial virus (RSV), and received FDA approval in 2023 to treat RSV in adults age 60 and older.¹¹ 

The first generation of COVID-19 vaccines were less effective against variants, including Omicron. New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters. A study of one vaccine in a randomized, double-blind and placebo-controlled Phase III trial in two stages found the vaccine was well-tolerated with an acceptable safety profile.¹³ Another study tested a vaccine in a randomized, placebo-controlled Phase I trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a fourth dose booster. Both vaccines showed a strong immune boosting response against beta, ancestral and Omicron strains.¹⁴ 

Viral Vector Vaccines

Viral vector vaccines employ genetically modified viruses to deliver genetic material-encoding antigens into host cells, prompting the immune system to generate protective responses against the targeted pathogen. Numerous viruses are deemed to be prominent viral vectors, including vesicular stomatitis virus, rabies virus, measles virus, Newcastle disease virus, influenza virus, adenovirus and poxvirus.¹⁵ 

RSV can lead to serious disease in infants. Currently, no approved RSV vaccine is available for infants. For adults, the first in-human Phase I clinical trial evaluated a single dose of BLB201, a PIV5-vectored RSV vaccine administrated via intranasal route, for safety and immunogenicity in RSV-seropositive healthy adults in three groups, ranging from 33 to 75 years of age, 70 percent of whom were female. The reported results suggested that BLB201 boosted RSV-specific serum Ab levels in young adults (33 to 59 years old) and elderly adults (61 to 75 years old), although with greater magnitude in young adults versus elderly adults. Runny noses, fatigue, headaches or myalgia were experienced by eight of the 45 participants. Chills, nausea/vomiting and breathing discomfort were reported by one participant. The study researchers concluded that the ability of BLB201 to boost pre-existing cellular, humoral and mucosal responses in adults supported further clinical evaluation.¹⁶

mRNA Vaccines

mRNA vaccines are used to treat COVID-19 (SARS-CoV-2), influenza, cytomegalovirus (CMV), Zika, cancer and various infectious diseases.

One study examined two Zika virus mRNA-based vaccines (mRNA-1325 and mRNA-1893), both of which were randomized, placebo-controlled, dose-ranging, multicenter, Phase I trials. All three dose levels of mRNA-1325 (10, 25 and 100 μg) were generally well-tolerated, but the vaccine elicited poor Zika virus-specific nAb responses. On day 57 of the mRNA-1893 vaccine trial, all evaluated dose levels induced robust Zika virus-specific nAb responses, independent of flavivirus serostatus, that persisted until month 13. The findings supported the continued development of mRNA-1893 against Zika virus.¹⁷

In February 2024, a group of cancer patients at Imperial College Healthcare NHS Trust Cancer UK underwent a new experimental mRNA therapy — a type of immunotherapy treatment called mRNA-4359 — which is being evaluated for safety and its potential for treating melanoma, lung cancer and other “solid tumor” cancers in a global trial. David Pinato, MD, PhD, a consultant medical oncologist at Imperial College Healthcare NHS Trust and a clinician scientist at Imperial College London, is lead investigator of the UK arm of the trial. He articulates the hope of these types of vaccines: “New mRNA-based cancer immunotherapies, such as mRNA-4359, offer a new avenue for recruiting patients’ own immune systems to fight their cancer. This research is still in the early stages and may be a number of years from being available to patients, but this trial is laying crucial groundwork that is moving us closer toward new therapies that are potentially less toxic and more precise.”¹⁸

DNA Vaccines

Deoxyribonucleic acid (DNA) vaccines utilize genetically engineered DNA to produce an immunologic response. They are used for cancer, tuberculosis, Edwardsiella tarda, human immunodeficiency virus (HIV), anthrax, influenza, malaria, dengue, typhoid and others.

In February 2024, researchers in one AIDS study found that the PD-1-enhanced DNA vaccination can induce sustained virus-specific CD8+ T cell immunity in an AIDS monkey model, and the vaccinated monkeys remained free of AIDS for six years and achieved virologic control without the need for combination antiretroviral therapy (cART) — a treatment used to suppress viral replication in individuals living with HIV. Study researchers say that if this efficacy can be replicated in humans, a therapeutic vaccine for cART-free HIV-1 control will be on the horizon.¹⁹

Typhoid remains a major health problem in the developing world. And it, too, has seen advances in a vaccine, one of which uses bacterial ghost (BG) technology, prepared by both genetic and chemical means. One report that showed improved preparation of high-quality BGs of Salmonella typhi, visualized by scanning electron microscope, revealed punctured cells with intact outer shells. Moreover, the absence of vital cells was confirmed by subculturing. At the same time, the release of respective amounts of proteins and DNA is another evidence of BGs’ production. Additionally, the challenge test provided evidence that the prepared BGs are immunogenic and have the same efficacy as the whole cell vaccine.²⁰

Hope for the Future

The remarkable achievements in successfully eradicating or in greatly curbing deadly diseases through vaccines in the past serve as a testament to the power of scientific innovation and collective action. Researchers remain vigilant in the face of evolving threats as they use cutting-edge advancements to develop vaccines for current and emerging diseases. By prioritizing global collaboration, innovation and equitable access to vaccines, hope is on the horizon for a healthier world.