Rallying against the pandemic
New vaccines arrive with swiftness and promise
While we have yet to see approved vaccines against the SARS-CoV-2 virus that causes COVID-19, the needle has definitely moved in a positive direction in the fight against the pandemic, with Emergency Use Authorization (EUA) granted by the US FDA for Moderna’s COVID-19 vaccine (mRNA-1273) and Pfizer’s and BioNTech’s COVID-19 vaccine (BNT162b2) since December.
Other countries and the European Union (EU) have made similar moves to authorize use of these products, and other vaccines are preparing to enter the fray as well, including Russia’s Sputnik V vaccine, for which Mexico is now considering fast-track authorization.
Among the companies vying to join Pfizer, BioNTech, and Moderna are OSE Immunotherapeutics, Arcturus, and AstraZeneca.
First out of the gate: Two mRNA approaches
Pfizer and BioNTech certainly started the buzz around breakthroughs in immunizing people against COVID when the partners announced in early November that BNT162b2 was more than 90-percent effective at seven days following the second dose of the vaccine, based on preliminary results from a late-stage clinical trial.
This certainly beat expectations for the scientific and healthcare community, as White House coronavirus advisor Dr. Anthony Fauci had said that even 50- or 60-percent effectiveness would be acceptable and many scientists and public health officials were hoping for at least 75-percent effectiveness.
The clinical data submitted by the companies for emergency use authorizations demonstrated a vaccine efficacy rate of nearly 95 percent in the companies’ Phase 3 clinical study in participants without prior SARS-CoV-2 infection (the first primary objective) and also in participants with and without prior SARS-CoV-2 infection (the second primary objective), in each case measured from seven days after the second dose.
According to the companies, efficacy was consistent across age, gender, race, and ethnicity demographics, with an observed efficacy in adults age 65 and over of more than 94 percent.
“While the data details are not clear at this time, there is no way not to celebrate this as a monumental achievement and a great first step forward towards controlling this devastating pandemic,” said Edward Jones-López, an infectious diseases expert at the University of Southern California’s Keck School of Medicine and one of the investigators in the Operation Warp Speed vaccine clinical trials, at the time of the announcement. “If the [efficacy estimate] is corroborated, the efficacy of this vaccine will be among the highest when compared to other very successful vaccines.”
The ongoing research by Pfizer and BioNTech on their messenger RNA (mRNA)-based vaccine has buoyed even more excitement, with efficacy rates seeming to remain very high and adverse reactions low. In addition, on Jan. 8 they announced results from an in-vitro study conducted by Pfizer and the University of Texas Medical Branch indicating that the antibodies from people who had received the COVID-19 vaccine effectively neutralize SARS-CoV-2 with a key mutation that is also found in two highly transmissible strains.
Moderna’s vaccine candidate, also mRNA-based, recently received approval from the United Kingdom’s Medicines and Healthcare products Regulatory Agency for temporary authorization, which followed similar actions on Moderna’s mRNA-1273 vaccine from the EU and Israel.
Moderna’s two-dose regime given 28 days apart reportedly has been well-tolerated as well, and it demonstrated vaccine efficacy of more than 94 percent against COVID-19. The vaccine encodes for a prefusion-stabilized form of the Spike protein of the virus, which was co-developed by Moderna and investigators from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.
Aside from the potential to stem the tide of the pandemic, the work by these companies could mean much for the development of other mRNA-based vaccines. “As no mRNA vaccines had been approved for human use, these clinical trials have created optimism in this research space,” noted data and analytics company GlobalData.
Other approaches to the coronavirus
Arcturus Therapeutics’ ARCT-021 investigational vaccine for COVID-19 is also mRNA-based, but that company has been angling for administration as a single injection rather than two, which would set it apart from the leading mRNA vaccine candidates if it shows sufficient efficacy.
Preclinical data for ARCT-021 have shown what the company calls “highly promising results” and a 100-percent seroconversion for neutralizing antibodies after a single administration using a low 2 µg dose. Neutralizing antibodies reportedly continued to increase for 60 days after dosing.
Arcturus began a Phase 1/2 study in late 2020. In Phase 1, escalating doses were to be administered as a single injection to younger adults aged 21 to 55 years old. Based upon the safety, immunogenicity, and T cell response data from this group, dose regimens would be selected for further evaluation in Phase 2, which includes cohorts in younger adults and older adults aged 56 to 80 years old.
As noted by GlobalData, Arcturus’ single-dose vaccine is reported to have demonstrated both humoral and cellular immunity to the vaccine antigen, at a relatively low dose level, “but it remains to be seen in future clinical trials whether the vaccine candidate can meet the high efficacy bar set by the frontrunners.”
Added GlobalData pharma analyst Keshalini Sabaratnam: “A single-dose vaccine with less stringent storage requirements that could be manufactured cost-effectively would be easier to distribute in low- and middle-income countries that cannot afford expensive vaccines and lack cold-chain services.”
For its part, OSE Immunotherapeutics is studying CoVepiT, a vaccine based on optimized epitopes selected to induce a lasting sentinel T lymphocyte immune response against SARS-CoV-2.
As noted by OSE in a November update on its work, scientists have warned of new SARS-CoV-2 variants that bear mutation in some key targets of the virus, in particular the Spike protein and nucleoprotein. Based on new analyses of some 167,000 different virus sequences taken globally, the OSE bioinformatics team said that it had confirmed that mutations did not emerge in the highly stable viral genome region of the 11 targets selected by OSE and that the CoVepiT vaccine continues to cover all initial and novel SARS-CoV-2 strains and variants.
“The identification of T memory immuno-dominant epitopes, selected for their high potential for immunogenicity, is a major step to move into clinical testing early 2021,” said Nicolas Poirier, chief scientific officer of OSE Immunotherapeutics.
AstraZeneca, meanwhile, has taken an adenovirus-vectored approach, employing a modified version of a common cold virus that usually only spreads among chimpanzees to carry a gene from the novel coronavirus’ Spike protein that, theoretically, will allow the human body to better mount an immune response to fight off the COVID virus.
In November, the company reported that one dosing regimen showed vaccine efficacy of 90 percent when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen showed 62-percent efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens resulted in an average efficacy of 70 percent. No serious safety events related to the vaccine had been confirmed, and AZD1222 was well tolerated across both dosing regimens.
While the overall efficacy doesn’t match what the two leading mRNA vaccines have achieved, AZD1222 does have an advantage in terms of storage.
“The storage conditions of mRNA vaccines are a critical issue, with Pfizer’s and Moderna’s vaccines requiring environments of -70°C and -20°C, respectively—although Moderna’s candidate is able to be stored at fridge and room temperatures for short periods of time,” noted GlobalData pharma analyst Mohamed Abukar. “ These low-temperature storage requirements increase the complexity of logistics, as there may not be enough low-temperature freezers available and shipping will require tracking using GPS-enabled thermal sensors to monitor the temperature of each shipment.”
But AZD1222 requires storage conditions between 2°C and 8°C, allowing for easier transportation and administration across a variety of settings. The vaccine has been approved for emergency use in the United Kingdom, India, and Mexico.
“Questions remain over the results obtained in the AZD1222 Phase 3 study, as the smaller second cohort presented with a superior efficacy of 90 perent compared with the 62 percent observed in the first group,” Abukar said. “However, the second group constitutes participants ages 55 and below, who may be less likely to become critically ill, which could allow for better efficacy results.”
The Sputnik V vaccine also takes the adenoviral vector-based platform approach. GlobalData notes that it has shown an efficacy of 95 percent in its Phase 3 trials, which is equal to that of the mRNA vaccines and requires storage conditions of -18°C or lower, similar to that of the Moderna vaccine; however, further trials are ongoing testing a freeze-dried version that could be stored between 2°C and 8°C. As GlobalData points out, higher storage temperature could be a competitive edge for the distribution of these vaccines.
Ethical and scientific concerns
However, while is heartening to see so many vaccines progressing so well in such a short span of time compared to traditional efforts in this prophylactic arena, some in the scientific community have raised concerns.
“The trickiest issue is to determine how the Pfizer vaccine—and other frontrunner candidates such as Moderna—results will affect the ethical and scientific integrity of the other ongoing vaccine studies,” noted USC’s Jones-López. “The ethical construct that is at the heart of all of these vaccines is the concept of ‘equipoise,’ which is only applicable if there are no vaccines that have been shown to be safe and effective, and available for the public to receive.
“Once one or more of these vaccines are approved based on scientific data showing they are both effective and safe, it becomes ‘unethical’ to continue offering placebo or to withhold an active vaccine. This tension is likely to complicate several of the ongoing studies and potentially threaten their scientific and ethical integrity.”
And while companies like Moderna have stressed that they plan to continue long-term studies of their vaccines no matter how soon approval might come—and that could be very soon for both of the two frontrunner vaccines given the urgency of the pandemic—various voices are being raised to emphasize the need to do that throughout the vaccine research community.
The European Medicines Agency, for example, endorsed a statement by the International Coalition of Medicines Regulatory Authorities (ICMRA) that urges all stakeholders—including vaccines researchers and investigators, academia, regulators, and the pharmaceutical industry—to continue COVID-19 vaccine trials beyond the time when the pre-defined cases of COVID-19 disease for final analysis in a trial have been reached.
‘The work of ICMRA in streamlining regulatory requirements for vaccines through global cooperation has supported the rapid development of COVID-19 vaccines,” said Emer Cooke, chair of ICMRA and EMA’s executive director. “Vaccines will be a key component in overcoming COVID-19, and we must ensure that robust and convincing evidence is being generated to enable the continuous assessment of their benefits and risks.”
The full statement—which can be found at www.icmra.info/drupal/covid-19/statement_on_continuation_of_vaccine_trials—states, in part:
“To determine that the benefit of a vaccine outweighs its potential risk, regulators need robust and convincing evidence of the safety and efficacy that is obtained from well-designed randomized and controlled trials. Initial positive evidence of the vaccine’s safety and efficacy used to support a regulatory action may be based on planned interim or final analyses that occur when a pre-defined number of cases of COVID-19 disease have occurred in a clinical trial. In these situations, it will be of the utmost importance to continue gathering data about the vaccine safety and efficacy in the longer-term after the interim or final analysis is completed.
“Specifically, continued follow-up of clinical trial participants after a regulatory decision has been made can provide important additional and more precise information on longer-term safety and efficacy against specific aspects of SARS-CoV-2 disease or infection, including efficacy against severe disease, efficacy in important subgroups, potential risks of vaccine-induced enhanced disease and whether protection against COVID-19 disease wanes over time.
“Thus, continued evaluation of the vaccinated and the unvaccinated (control subjects who do not receive a vaccine against COVID-19) groups in clinical trials for as long as feasible will provide invaluable information.
“For these reasons, investigators and sponsors should develop strategies to ensure continuation of follow-up of vaccinated and control groups for as long as possible after any regulatory approval that is based on planned analyses conducted while trials are still ongoing and after final analyses are completed.”
Moderna announces three new mRNA-based infectious disease vaccines
CAMBRIDGE, Mass.—Biotech company Moderna Inc. isn’t just making news with a COVID-19 vaccine candidate but also three other potential vaccines based around its messenger RNA (mRNA) technology.
In January, the company announced that it is expanding its vaccine pipeline with three new development programs based on the clinical success of its infectious disease vaccine portfolio to date and its experience with its COVID-19 vaccine. Those three new programs—all of them mRNA vaccine candidates—are against seasonal flu, HIV and the Nipah virus (NiV). In conjunction with this, Moderna also announced an expansion of its respiratory syncytial virus (RSV) vaccine program into older adults.
“The uniquely challenging year of 2020 for all of society proved to be an extraordinary proof-of-concept period for Moderna,” said Stéphane Bancel, CEO of Moderna. “Even as we have shown that our mRNA-based vaccine can prevent COVID-19, this has encouraged us to pursue more ambitious development programs within our prophylactic vaccines modality ... seasonal flu, HIV and the Nipah virus, some of which have eluded traditional vaccine efforts, and all of which we believe can be addressed with our mRNA technology.”
Moderna currently has 24 mRNA development programs in its portfolio, with 13 having entered the clinic. Highlights of the three new programs are as follows:
- Flu vaccine (mRNA-1010, mRNA-1020, mRNA-1030): The company’s first-generation flu program will evaluate multiple candidates comprising multiple antigen combinations against the four seasonal viruses recommended by the World Health Organization. Moderna expects to begin Phase 1 clinical trials for the program in 2021. The company also plans to explore potential combination vaccines against flu, SARS-CoV-2, RSV, and human metapneumovirus.
- HIV vaccine (mRNA-1644 & mRNA-1574): The mRNA-1644 vaccine involves a collaboration with the International AIDS Vaccine Initiative and the Bill and Melinda Gates Foundation and represents a novel approach to HIV vaccine strategy in humans, as it is designed to elicit broadly neutralizing HIV-1 antibodies. A Phase 1 study for mRNA-1644 will use iterative human testing to validate the approach and antigens and multiple novel antigens will be used for germline-targeting and immuno-focusing. A second approach, mRNA-1574, is being evaluated in collaboration with the National Institutes of Health (NIH) and includes multiple native-like trimer antigens. The company expects to begin Phase 1 clinical trials for both mRNA-1644 and mRNA-1574 in 2021.
- Nipah virus vaccine (mRNA-1215): NiV is a zoonotic virus transmitted to humans from animals, contaminated food, or through direct human-to-human transmission that causes a range of illnesses, including fatal encephalitis. Severe respiratory and neurologic complications of NiV have no treatment other than intensive supportive care. This candidate was co-developed by Moderna and the NIH’s Vaccine Research Center.
Moderna’s pipeline is organized into six modalities based on similar mRNA technologies, delivery technologies and manufacturing processes. The company’s approach is to leverage early programs within a modality to generate clinical data and insights that reduce the technology risk of subsequent programs and accelerate the expansion of the pipeline in that modality.
According to the company, positive Phase 1, 2, and 3 data from Moderna’s infectious disease vaccine portfolio and positive Phase 1 data from its chikungunya antibody program have de-risked its prophylactic vaccines and its systemic therapeutics and cell surface modalities, respectively. Beyond these core modalities, Moderna has four exploratory modalities in which it is actively pursuing clinical proof of concept.
Boosting a vaccine designed to prevent melanoma recurrence
NEW YORK—A vaccine created to prevent the recurrence of the deadly skin cancer melanoma is about twice as effective when patients also receive two components that boost the number and effectiveness of immune system cells called dendritic cells, according to Phase 2 clinical trial results published in Nature Cancer in November.
These results are potentially important because most cancer vaccine trials have failed to show clinical efficacy. These results suggest that adding two immune-boosting components can boost the immune response for not only melanoma patients but possibly also others whose cancers express a protein called the vaccine antigen, which is common in some cancers.
Researchers at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, working with colleagues at the National Cancer Institute-funded Cancer Immunotherapy Trials Network (CITN) based at the Fred Hutchinson Cancer Research Center, found that adding the small molecule Flt3L, which increases the number of dendritic cells, boosted the vaccine’s effectiveness at producing antibodies and T cells that can later fight melanoma. Adding a second component, called poly-ICLC, also strengthened the dendritic cells’ ability to promote antibodies as well as helper and killer T cells.
The vaccine is designed to target dendritic cells and is composed of an antigen found in melanoma bound to an antibody to increase the chances of binding with dendritic cells.
Sixty patients who had stage 2 or 3 melanoma, and whose cancer was successfully removed via surgery, received the vaccine. Half of the patients received the vaccine alone while the other half received the vaccine with Flt3L and poly-ICLC.
The cocktail of the vaccine, Flt3L, and poly-ICLC nearly doubled the vaccine’s efficacy, according to analysis of the T cells detected in patients’ blood samples after they received four doses over four months. That immune response was seen significantly earlier in the patients who received the cocktail and at much higher levels in many more patients compared to those who received only the vaccine. Researchers found antibodies were still present in blood samples tested 12 weeks after the last dose.
“This is the first randomized clinical trial to show that an immune response to a cancer vaccine can be potentiated by the addition of Flt3L,” said Dr. Nina Bhardwaj, director of the Immunotherapy Program at The Tisch Cancer Institute and first author and a corresponding author on the study. “The response was achieved because Flt3L mobilized dendritic cells, which are the gold standard in promoting cancer immunity, and improved the overall immunogenicity of the vaccine. This may change the approach of increasing efficacy in other cancer vaccines in the future.”
Added Dr. Steven Fling, director of the CITN Laboratory, a scientist at the Fred Hutchinson Cancer Research Center, and the study’s co-corresponding and senior author: “These positive results are significant not only for improving cancer vaccines, but also potentially for application to other vaccine platforms, and we are extremely grateful and indebted to the patients whose unwavering participation made this demanding clinical protocol a success.”
These findings also provide a basis for adding checkpoint inhibitors, which have been successful in treating metastatic melanoma, to vaccines in order to further increase the success in fending off melanoma recurrence. Researchers also plan to follow trial participants over time and measure how many have cancer recurrence to further study the vaccine’s efficacy in each group.
“Immunotherapy has already shown great promise for patients with metastatic melanoma who would normally have a difficult, sometimes grave, prognosis,” said Dr. Philip Friedlander, director of the Melanoma Medical Oncology Program at The Tisch Cancer Institute at Mount Sinai and site investigator of the trial. “It’s important to work toward developing effective cancer vaccines that can prevent cancer on their own or in addition to the drugs already available.”
Intravacc publishes positive Phase 1 Shigella conjugate vaccine data
BILTHOVEN, The Netherlands—Intravacc, a translational research and development vaccine institute with an extensive track record in developing viral and bacterial vaccines, in late 2020 announced the results of a clinical study with an experimental vaccine against Shigella, intestinal bacteria that cause the extremely contagious condition shigellosis, which results in severe diarrhea and dysentery.
Data were published in the journal The Lancet Infectious Diseases. The paper was authored by a team of researchers and clinicians at Tel Aviv University, Tel Aviv Sourasky Medical Center, Institut Pasteur, Ariel University, and Intravacc. The clinical study in healthy adults shows that the vaccine is well tolerated and immunogenic.
Currently there is no vaccine available against Shigella. This experimental vaccine (SF2a-TT15), developed by Institut Pasteur, is a conjugate vaccine consisting of a synthetic oligosaccharide chemically linked to tetanus toxoid. The oligosaccharide mimics a part of bacterial lipopolysaccharide (LPS), which is abundantly present in the outer membrane of Shigella bacteria.
“We are very pleased with the results of this Phase 1 study. We are able to do this because of our unique expertise in conjugate vaccine development,” said Dr. Virgil Schijns, Intravacc’s chief scientific officer. “This now allows us to continue with a human challenge model and a Phase 2 study in children.”
The vaccine was given three times to 64 seronegative volunteers in two doses and with and without aluminium hydroxide adjuvant. Both doses induced significantly increased serum IgG titres as well as an increase in memory B cells. The non-adjuvanted high dose induced a 25-fold increase in IgG GMT after one injection while the non-adjuvanted low dose induced a fivefold increase, compared with baseline.
Alum significantly enhanced the specific IgG response at both doses after the 3rd injection. At high dose, the vaccine also induced a fouefold or greater rise in serum bactericidal titres in 80 percent of the volunteers receiving the adjuvanted dose and in 100 percent of those receiving the non-adjuvanted vaccine.
Only mild adverse effects were reported.
About 250 million cases of shigellosis occur annually in low and middle-income countries. No group of individuals is immune to shigellosis, but certain individuals are at increased risk. Small children acquire Shigella infection at the highest rate. The infection is easily spread because of its low infectious dose, and spreading typically occurs via the oral-faecal route both by person-to-person contact and through eating contaminated food.
AIVITA’s glioblastoma vaccine shows improved PFS
IRVINE, Calif.—AIVITA Biomedical Inc., a private biotechnology company specializing in innovative stem cell applications, in late 2020 announced data from its multicenter Phase 2 clinical trial of its personalized cancer vaccine, AV-GBM-1, in patients with newly diagnosed glioblastoma (GBM).
The analysis focused on 57 patients who were scheduled to receive up to eight doses of AV-GBM-1 over approximately six months. At the time of the analysis, surviving patients had completed therapy and had been followed between 7.2 and 24.2 months. The median length of progression-free survival (PFS) was 10 months, an improvement of approximately 45 percent compared to a median of 6.9 months PFS in the landmark study that established the standard of care for patients with newly diagnosed GBM. This represented a 38-percent reduction in risk of progression or death at 6.9 months of treatment.
“The improvement in glioblastoma patients who were treated with AV-GBM-1, compared to studies with the standard of care, is a very promising indication that our therapy confers benefit to patients in need,” said Dr. Robert O. Dillman, chief medical officer of AIVITA.
AV-GBM-1 is a novel immunotherapy consisting of autologous dendritic cells loaded with autologous tumor antigens derived from self-renewing tumor-initiating cells. The treatment is administered in a series of subcutaneous injections. The treatment is uniquely pan-antigenic, targeting multiple antigens from autologous tumor-initiating cells that are responsible for the rapid growth of the disease.
“This is a major victory against glioblastoma, a devastating disease that has evaded treatment for far too long,” added Dr. Hans S. Keirstead, CEO of AIVITA. “We now have excellent results from Phase 2 clinical studies in both melanoma and glioblastoma, underscoring the tremendous potential of this personalized cancer immunotherapy.”
AIVITA is also currently conducting three clinical studies in the United States investigating its platform immunotherapy in patients with ovarian cancer, glioblastoma, and melanoma. AIVITA is also seeking conditional commercial approval of its melanoma treatment in Japan.