Vaccines are the cornerstone in our defense against microbial pathogens that are widely recognized as causing substantial economic burden on society.1 It can often take more than 10 years and between $200 million and $500 million to produce a vaccine; however, vaccines have become the most cost-effective health intervention with the greatest success rates.2,3 Indeed, in 2006, the World Health Organization (WHO) and United Nations International Children’s Fund launched the Global Immunization Vision and Strategy, with the aim of controlling morbidity and mortality from vaccine-preventable diseases, including the introduction of technologies and vaccines that have recently become available.4 Additionally, the WHO’s Strategic Advisory Group of Experts on Immunization created the Global Vaccine Action Plan 2011-2020 to realize the goal of allowing communities to live free from vaccine-preventable diseases.5

To facilitate the creation and dissemination of new vaccines, the WHO maintains a list of all vaccines in the “pipeline” for clinical trials.6 Currently, a total of 2612 vaccines are being investigated for a number of infectious diseases, including respiratory syncytial virus, dengue fever, and malaria; however, this article will focus on reviewing the vaccine pipeline for the following viruses: Zika, Ebola, Lassa, Nipah, Middle East respiratory syndrome coronavirus (MERS-CoV), HIV, and coronavirus disease 2019 (COVID-19).6,7

The Zika virus belongs to the genus Flavivirus. It is transmitted by Aedes mosquitoes, which are mainly found in tropical, subtropical, and some temperate climates.8,9 Disease caused by this virus is usually mild; however, severe complications are associated with infection, such as Guillain-Barré syndrome and congenital neurological abnormalities, which have been extensively reported on in recent years.9 For example, the results of a 2018 study by Nielsen-Saines and colleagues found that of 131 infants whose mothers tested positive for Zika while pregnant, a total of 6.25% had eye abnormalities, 12.2% had hearing problems, and 11.7% had severe delays in motor, language, and/or cognitive function by 12 to 18 months of age.10 According to the CDC, between 2015 and 2018, 2490 pregnant women had evidence of possible Zika infection in the United States. Of their liveborn children, 116 had Zika-associated birth defects.10

Currently, 7 unique vaccines against Zika virus are actively being investigated, according to the WHO, with 5 of these in phase 1 trials and 2 of these in phase 2 trials.6

The vaccine that is furthest along is VRCZKADNA090- 00-VP, a 3-dose, DNA-based vaccine targeting the prME protein in the Zika virus.6 A study on this vaccine is being conducted in young adults and adults aged 15 to 35 years in the United States and Puerto Rico. As of January 2020, recruitment has been completed for this trial, and results are pending.11

The Ebola viruses are a group of viruses within the genus Ebolavirus and are transmitted through exposure to infected body fluid from humanto- human or animal-to-human contact.12 Ebola virus disease carries a high mortality rate; up to 90% of patients infected with the Zaire ebolavirus species of the virus will die.12 Outbreaks have historically occurred in Africa, and the most recent and second largest outbreak of Ebola is still active in the Democratic Republic of Congo.13

According to the WHO, 6 unique vaccines and 22 trials are actively being investigated in varying phase 1 through phase 4 trials.6 The 2 vaccines that are commercially available for prevention of infection by Zaire ebolavirus include the GamEvac-Combi vaccine (dose 1: VSV-GP; dose 2: Ad5-GP) in Russia and the rVSV-ZEBOV vaccine (Ervebo) in the United States, Africa, and Europe.6,13-16 The rVSV-ZEBOV vaccine was FDA approved on December 19, 2019,13 and is a live, recombinant vaccine that targets the glycoprotein envelope of Zaire ebolavirus. The duration of protection once the vaccine has been given is currently unknown17; however, Ervebo has shown to be 100% effective after vaccination in preventing the onset of symptoms after more than 10 days.13

MERS-CoV, the virus that causes Middle East respiratory syndrome (MERS), is a member of the genus Betacoronavirus and is transmitted through droplets spread by close contact with infected individuals.18,19 People who become infected with MERS-CoV can present with mild symptoms similar to the common cold or severe symptoms such as a respiratory illness manifesting as fever, cough, and shortness of breath.20 Other severe manifestations of this disease are diarrhea, nausea and vomiting, pneumonia, and kidney failure.20

In the United States, there have only been 2 reported cases of MERS since 2014, both of which were individuals who lived and worked in Saudi Arabia as health care providers.21 Significant outbreaks of MERS have occurred in Saudi Arabia and South Korea, and 27 other countries have reported cases. The WHO is focused on developing countermeasures due to the 30% fatality rate.22

There are currently 2 vaccines against this virus, the first of which has completed a phase 1 trial (NCT02670187). Several different doses of the vaccine were administered to healthy patients, followed by localized intramuscular electroporation to increase the DNA uptake of the vaccine.23 The vaccine was administered 3 separate times: at baseline, 4 weeks, and 12 weeks. Study authors concluded that the immune response was dose independent, with 2 doses eliciting an immune response in more than 85% of participants and lasting for at least a year.24 Phase 2 trials have yet to be registered with or the WHO.

The second vaccine candidate is MVA-MERS-S (NCT03615911), which is in phase 1 of first-in-human trials. The vaccine was administered to 24 patients on days 0 and 28. Twelve received 107 plaque-forming units (PFU), and the other 12 received 108 PFU. Nine months after immunization, a subgroup of patients from each group received a late booster immunization of 10^8 PFU.25 MVA-MERS-S was found to be favorably safe and without serious or severe adverse events, but the official results have not yet been made available to the public.25,26

Human immunodeficiency virus (HIV) is a member of the genus Lentivirus and is transmitted through contact with infected body fluids.27,28 People who become infected with HIV may initially present with cold or flulike symptoms, but others may not present any symptoms in the first stage of HIV. In the second stage of HIV, patients may still be asymptomatic and, without medicine, this stage can last for more than 10 years. If patients take HIV medicine, they may not move onto stage 3 or acquired immunodeficiency syndrome (AIDS) of the disease; however, if a patient enters stage 3, their immune system will have already been severely damaged.29 HIV slowly destroys CD4+ T cells, which weakens the immune system and leads to infections from opportunistic organisms, such as Cryptococcus neoformans, Pneumocystis jiroveci, and Candida albicans.29,30

The CDC recommends testing at least once for all patients aged 13 to 64 years and among those who are at high risk of infection, such as injection drug users or individuals who have had multiple sexual partners.31 However, the results of a recent study by the CDC which analyzed 2016-2017 US data found that of adults aged older than 18 years, only 38.9% had ever been tested for HIV. For those who fall under the recommendation criteria (n = 15,791), only 64.8% were tested.32

Initial vaccine trials for HIV have been ongoing since 1987.33 Some difficulties with creating an effective HIV vaccine include creating an appropriate vaccine that will not mutate with the virus, accounting for many different subtypes of the virus throughout the world, and eliciting an effective immune response through stimulating antibody production, cellular immune response, and innate immune response.34 Despite these adversities, there are 41 unique vaccines actively being investigated in various phase 1, phase 1b, phase 1/2a, phase 1/2, phase 2, phase 2b, and phase 2b/3 trials.6 The vaccine furthest along is ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59.35 This vaccine is a recombinant protein that contains genes from HIV as well as MF59, a known vaccine adjuvant that stimulates a stronger immune response.35 The trial with this vaccine—currently taking place in Mozambique, South Africa, and Zimbabwe—is scheduled to be completed in August 2021.6

The severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) is a member of the genus Betacoronavirus and is transmitted through droplets spread by close contact with infected individuals.36,37 SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19).38 People who become infected with SARS-CoV-2 have a range of symptoms that could be asymptomatic or could include fever, chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, and congestion or runny nose, which may eventually lead to respiratory failure and death.39-41 The overall rate of hospitalization in patients who received a diagnosis with COVID-19 is 137.6 per 100,000 people, with a mortality rate of 7.8% during week 31 of the 2020 pandemic.42 As of August 11, 2020, there have been 161,842 deaths and 5,023,694 total cases of COVID-19 in the United States.41

Currently 143 vaccines are actively being investigated, with 1 in phase 0, 12 in phase 1, 56 in phase 2, and 25 in phase 3.7 The AZD1222 vaccine, created by the University of Oxford and manufactured by AstraZeneca, is currently in phase 3 trials.43

On July 13, 2020, the FDA fast-tracked 2 of the most advanced vaccines that are being developed by Pfizer and BioNTech: BNT162b1 and BNT162b2.44 Phase 2b/3 trials were expected to start late July 2020, and by the end of the year, the companies are set to manufacture up to 100 million doses. By the end of 2021, they expect to have more than 1.2 billion doses.44

The Lassa virus is carried by a rodent known as the multimammate rat (Mastomys natalensis) and can be transmitted to humans through direct contact, ingestion of the animal or contaminated food, and inhalation of air contaminated with urine or droppings during cleaning activities, such as sweeping.45 Lassa fever, the zoonotic, acute viral illness that results from infection, primarily affects people living in West Africa (where the rat resides), causing 10% to 16% of annual hospitalizations.46 The Lassa virus is a member of the family Arenaviridae and causes mild fever, malaise, weakness, and headache; however, severe cases may cause hemorrhaging; breathing problems; vomiting; facial swelling; pain in the chest, back, and abdomen; shock; and deafness.47,48 The mortality rate is 15% to 20% of hospitalized patients.48 Each year there are an estimated 100,000 to 300,000 cases of Lassa fever and approximately 5,000 deaths around the world.46 Symptoms can appear 1 to 3 weeks after exposure, and because 80% of patients experience mild symptoms, the virus can go unidentified and unreported.48

According to the WHO’s tracking site, no active vaccines are currently targeting the Lassa virus.6

The Nipah virus is a member of the genus Henipavirus and is transmitted through direct contact with infected bats, pigs, or people. People who become infected with the Nipah virus can present with encephalitis, with the beginning of the illness presenting with fever, headache, drowsiness, disorientation, mental confusion, and sometimes respiratory illness.49-51 According to the WHO’s tracking site, no active vaccines are currently targeting the Nipah virus.6

Vaccines are the safest and most effective prevention against infectious diseases, but further research and development are required. The Global Vaccine Action Plan 2011-2020 concluded its work this year, and one of its high-level recommendations included preparing to give populations the vaccines and care they need by planning for future development and implementation of vaccines.5 These benefits encompass not just the direct benefit of disease avoidance but also indirect benefits, including a reduction in medical and socioeconomic burden, quality of life associated with long-term adverse effects of infection, and antibiotic resistance development through reduction in antibiotic use in food-producing animals.52 Continued efforts by the WHO and other local organizations are needed to support and sustain vaccine research and development.
JAMIE L. WAGNER, PHARMD, BCPS, is a clinical assistant professor of Pharmacy Practice at the University of Mississippi School of Pharmacy in Jackson, Mississippi.

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