The world’s biggest COVID-19 vaccine study got underway Monday with the first of 30,000 planned volunteers helping to test shots created by the U.S. government – one of several candidates in the final stretch of the global vaccine race.
There’s still no guarantee that the experimental vaccine, developed by the National Institutes of Health and Moderna Inc., will really protect.
The needed proof: Volunteers won’t know if they’re getting the real shot or a dummy version. After two doses, scientists will closely track which group experiences more infections as they go about their daily routines, especially in areas where the virus still is spreading unchecked.
“Unfortunately for the United States of America, we have plenty of infections right now” to get that answer, NIH’s Dr. Anthony Fauci recently told The Associated Press.
Moderna said the vaccination was done in Savannah, Georgia, the first site to get underway among more than seven dozen trial sites scattered around the country.
Several other vaccines made by China and by Britain’s Oxford University earlier this month began smaller final-stage tests in Brazil and other hard-hit countries.
But the U.S. requires its own tests of any vaccine that might be used in the country and has set a high bar: Every month through fall, the government-funded COVID-19 Prevention Network will roll out a new study of a leading candidate – each one with 30,000 newly recruited volunteers.
The massive studies aren’t just to test if the shots work – they’re needed to check each potential vaccine’s safety. And following the same study rules will let scientists eventually compare all the shots.
Next up in August, the final study of the Oxford shot begins, followed by plans to test a candidate from Johnson & Johnson in September and Novavax in October – if all goes according to schedule. Pfizer Inc. plans its own 30,000-person study this summer.
That’s a stunning number of people needed to roll up their sleeves for science. But in recent weeks, more than 150,000 Americans filled out an online registry signaling interest, said Dr. Larry Corey, a virologist with the Fred Hutchinson Cancer Research Institute in Seattle, who helps oversee the study sites.
“These trials need to be multigenerational, they need to be multiethnic, they need to reflect the diversity of the United States population,” Corey told a vaccine meeting last week. He stressed that it’s especially important to ensure enough Black and Hispanic participants as those populations are hard-hit by COVID-19.
It normally takes years to create a new vaccine from scratch, but scientists are setting speed records this time around, spurred by knowledge that vaccination is the world’s best hope against the pandemic.
The coronavirus wasn’t even known to exist before late December, and vaccine makers sprang into action Jan. 10 when China shared the virus’ genetic sequence.
Just 65 days later in March, the NIH-made vaccine was tested in people. The first recipient is encouraging others to volunteer now.
“We all feel so helpless right now. There’s very little that we can do to combat this virus. And being able to participate in this trial has given me a sense of, that I’m doing something,” Jennifer Haller of Seattle told the AP.
“Be prepared for a lot of questions from your friends and family about how it’s going, and a lot of thank-you’s.”
That first-stage study that included Haller and 44 others showed the shots revved up volunteers’ immune systems in ways scientists expect will be protective, with some minor side effects such as a brief fever, chills and pain at the injection site.
Early testing of other leading candidates have had similarly encouraging results.
If everything goes right with the final studies, it still will take months for the first data to trickle in from the Moderna test, followed by the Oxford one.
Governments around the world are trying to stockpile millions of doses of those leading candidates so if and when regulators approve one or more vaccines, immunizations can begin immediately.
But the first available doses will be rationed, presumably reserved for people at highest risk from the virus.
“We’re optimistic, cautiously optimistic” that the vaccine will work and that “toward the end of the year” there will be data to prove it, Dr. Stephen Hoge, president of Massachusetts-based Moderna, told a House subcommittee last week.
Until then, Haller, the volunteer vaccinated back in March, wears a mask in public and takes the same distancing precautions advised for everyone – while hoping that one of the shots in the pipeline pans out.
“I don’t know what the chances are that this is the exact right vaccine. But thank goodness that there are so many others out there battling this right now,” she said.
Adverse Events of Special Interest (AESIs) (serious or non-serious) are events of significant medical and scientific concern specific to the sponsor’s program or product.
These require ongoing monitoring and communication by the investigator to the sponsor and might require further investigation to characterize and understand them; and rapid communication by the trial sponsor to regulators.
They could be related to vaccines in general, specific vaccine platforms or the disease. AESIs reporting and assessment is done with high priority as they could change the benefit-risk profile of the vaccine or require prompt public communication.
For the COVID-19 vaccines, the AESIs could potentially include vaccine-enhanced disease (vaccination could make subsequent infection with SARS-CoV-2 more severe) .
Enhanced disease, with a few deaths, was associated with the Dengue vaccine and had been reported with formalin-inactivated respiratory syncytial virus (RSV) vaccine in young children who received the vaccine and were subsequently infected with natural RSV in 1967.
Enhanced disease was seen in some preclinical studies with SARS-CoV vaccines and raised questions about other coronavirus vaccines showing a similar AESI. Other AESIs relevant to COVID-19 disease could potentially include respiratory (including pneumonia, acute respiratory distress syndrome), cardiac (including cardiogenic shock, cardiomyopathy, arrhythmia, coronary artery disease, myocarditis and pericarditis), acute renal, and hepatic injury, neurological (including encephalopathy, encephalitis, GBS, anosmia and ageusia), sepsis and septic shock, hypercoagulability, rhabdomyolysis and multisystem inflammatory syndrome in children .
AESIs related to novel adjuvants and vaccine platforms (e.g. cardiac AE including myo/pericarditis with MVA, and arthritis with VSV platforms); and vaccination (e.g. anaphylaxis, thrombocytopenia, seizures, GBS) should also be considered.
An adverse event following immunization (AEFI) is “any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine”.
AEFIs include the background rate of all diseases post-vaccination and may include excess burden of these diseases if the vaccine causes a vaccine adverse reaction. Safety surveillance must be capable of investigating AEFIs and AESIs as our understanding of the biological mechanisms for adverse reactions has limitations and we must anticipate coincidental events that clinicians, the media and the public may attribute to the vaccine.
Safety surveillance must be able to detect and rapidly investigate AESIs and AEFIs to determine if the temporal relationship is causal or coincidental.
Preparations need to be made now in order to ensure that emergency vaccine use in accompanied with robust vaccine safety surveillance and a process for safety assessment which will maintain public confidence in the vaccine.
The vaccine will likely be used with COVID-19 widely circulating. Thus safety surveillance will need to distinguish between health outcomes caused by the disease versus those caused by the vaccine.
Real or coincidental AESIs and AEFIs have the potential to undermine the vaccine program and exacerbate public fear around the pandemic.
Active and sentinel surveillance systems are necessary to rapidly and rigorously evaluate the safety profile of the vaccines. Many high-income countries have large healthcare administrative databases to conduct such active surveillance and have vaccine experience.
However, low-and middle-income countries (LMIC) generally lack the capacity to conduct active safety surveillance and do not have large healthcare administrative databases.
As equitable access to the vaccines for people during epidemics is imperative, active safety surveillance in LMIC is critical to ensure that safety surveillance is also equitable.
As was done prior to launch of the 2009–2010 H1N1 vaccines, active surveillance systems should calculate the incidence of background rates of AESI prior to vaccine roll out .
Establishing these background rates of disease prior to vaccination allows for a stable rate, based upon multiple years of data, so that the rates of these outcomes after vaccine roll out can be compared.
CEPI is developing a comprehensive list of AESIs. The incidence of these outcomes will vary tremendously based upon the region, underlying population, and methods use for case ascertainment which will be highly dependent on the characteristics of the active or sentinel surveillance system.
Surveillance in LMIC must be established now, in preparation for vaccine roll out, so that background rates of AESIs can be calculated.
There are several approaches that can be used to establish active surveillance systems in LMIC. There is very limited access to large healthcare administrative databases in LMIC.
India and South Africa (the only country in Africa) have such administrative databases though with limited vaccine safety experience. Other LMIC have registries or sentinel site-based surveillance capacity, such as hospital surveillance, that can be very useful for some outcomes.
There are a large number of international collaborations with LMIC institutions that have the potential to be used as active vaccine safety surveillance sites.
For example, the NIH Fogarty International Center Global Health Program has over 80 partner LMIC institutions and many academic institutions have well established sites in LMIC.
Such sites require a defined population and local capacity to collect primary data. Efficiencies can be accomplished by global standards for AESIs and development of harmonized case definitions (as is being done by the Brighton Collaboration under contract with CEPI).
However, the time is now to develop these sites for vaccine safety assessment and calculate background rates prior to vaccine introduction.
It is also essential that countries and regions plan for real and coincidental AESIs and AEFIs with a scientifically rigorous and publicly credible process to separate real adverse reactions from coincidental background rates of disease.
Safety signals require careful evaluation often involving chart review of potential cases, which can be both time and labor intensive. As recommended by the WHO Global Vaccine Safety Blueprint (GVSB 2.0), “Countries or regions establish either a national expert committee for AEFIs or regional advisory committees or equivalent objective panels with spelled out terms of reference .”
Public credibility can be optimized by ensuring that these committees are “independent of conflicts of interest with the ministries of health, industry and the immunization program”. Vaccine safety communication plans, with clear national and subnational vaccine safety communication roles and responsibilities, should be developed to provide timely, evidence-based messaging to describe what is known, what is not known, and what is being done to fill these gaps.
mRNA-1273 is an mRNA vaccine against COVID-19 encoding for a prefusion stabilized form of the Spike (S) protein, which was selected by Moderna in collaboration with investigators from the VRC.
The first clinical batch, which was funded by the Coalition for Epidemic Preparedness Innovations, was completed on February 7, 2020 and underwent analytical testing; it was shipped to NIH on February 24, 42 days from sequence selection.
The first participant in the NIAID-led Phase 1 study of mRNA-1273 was dosed on March 16, 63 days from sequence selection to Phase 1 study dosing. On May 12, the FDA granted mRNA-1273 Fast Track designation.
Both cohorts, healthy adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300), in the Company’s Phase 2 study of mRNA-1273 are fully enrolled.
After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group).
After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively).
After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.
Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.
Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination.
After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group; all were mild or moderate in severity (Figure 1 and Table S2).
Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.
None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever; one of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.)
Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.
Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3).
“These positive Phase 1 data are encouraging and represent an important step forward in the clinical development of mRNA-1273, our vaccine candidate against COVID-19, and we thank the NIH for their ongoing collaboration.
The Moderna team continues to focus on starting our Phase 3 study this month and, if successful, filing a BLA,” said Stéphane Bancel, Chief Executive Officer of Moderna.
“We are committed to advancing the clinical development of mRNA-1273 as quickly and safely as possible while investing to scale up manufacturing so that we can help address this global health emergency.”
Both cohorts, healthy adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300), in the Company’s Phase 2 study of mRNA-1273 are fully enrolled. This Phase 2 placebo-controlled, dose-confirmation study is evaluating the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. Each participant is receiving placebo, a 50 μg or a 100 μg dose at both vaccinations.
The Phase 3 study protocol has been reviewed by the U.S. Food and Drug Administration (FDA) and is aligned to recent FDA guidance on clinical trial design for COVID-19 vaccine studies.
The randomized, 1:1 placebo-controlled trial is expected to include approximately 30,000 participants at the 100 µg dose level in the U.S. The primary endpoint will be the prevention of symptomatic COVID-19 disease.
Key secondary endpoints include prevention of severe COVID-19 disease (as defined by the need for hospitalization) and prevention of infection by SARS-CoV-2. The primary efficacy analysis will be an event-driven analysis based on the number of participants with symptomatic COVID-19 disease.
The target vaccine efficacy (VE) against COVID-19 for powering assumptions is 60% (95% confidence interval to exclude a lower bound >30%).
Data will be reviewed by an independent Data Safety Monitoring Board organized by NIH.
The trial is expected to have two interim analyses (at approximately 53 and 106 events), prior to a final event-driven analysis, at approximately 151 events. This Phase 3 study has been named the COVE study.
The ClinicalTrials.gov identifier is NCT04470427. We anticipate sites to be initiated from July 21st and for enrollment into the study to commence on July 27.
Moderna is working closely with Operation Warp Speed (OWS) and the NIH, including NIAID’s COVID-19 Prevention Trials Network (COVPN), to conduct the Phase 3 COVE study. Working together with collaborators like NIH, the Company hopes to achieve a shared goal that the participants in the COVE study are representative of the communities at highest risk for COVID-19 and of our diverse society.
Moderna has completed manufacture of vaccine required to start the Phase 3 study. With the Phase 3 dose being finalized at 100 μg, the Company remains on track to be able to deliver approximately 500 million doses per year, and possibly up to 1 billion doses per year, beginning in 2021 from the Company’s internal U.S. manufacturing site and strategic collaboration with Lonza.
In addition, Moderna recently announced a collaboration with Catalent for large-scale, commercial fill-finish manufacturing of mRNA-1273 at Catalent’s biologics facility in Indiana.
On July 9, Moderna announced a collaboration with ROVI for large-scale, commercial fill-finish manufacturing of mRNA-1273 intended in principle to supply markets outside of the U.S. starting in early 2021 at ROVI’s facility in Madrid, Spain.
Funding from the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services (HHS), partially supported the planning for the Phase 2 and Phase 3 studies of mRNA-1273 and is supporting the execution of these studies, as well as the manufacturing process scale-up of mRNA-1273.
Moderna will also fund costs required to complete the development of mRNA-1273 including portions of the Phase 3 study and the scale up of manufacturing capacity at the final established dosage in order to obtain licensure for mRNA-1273. A summary of the company’s work to date on COVID-19 can be found here.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including regarding the Company’s development of a potential vaccine against the novel coronavirus, the parameters of the Phase 1 and Phase 2 studies of mRNA-1273, the publication of study data for later cohorts in the Phase 1 study of mRNA-1273, the parameters and timing of the Phase 3 study of mRNA-1273, the potential filing of a biologics license application (BLA) for mRNA-1273, the Company’s potential manufacturing capabilities and projected vaccine dose production, and costs related to the mRNA-1273 program to be funded by the Company. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “could”, “expects,” “intends,” “plans,” “aims,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Moderna’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others: the fact that there has never been a commercial product utilizing mRNA technology approved for use; the fact that the rapid response technology in use by Moderna is still being developed and implemented; the fact that the safety and efficacy of mRNA-1273 has not yet been established; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and clinical trials, supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those other risks and uncertainties described under the heading “Risk Factors” in Moderna’s most recent Quarterly Report on Form 10-Q filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SEC’s website at www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on Moderna’s current expectations and speak only as of the date hereof.
Table 1: Binding Antibodies Geometric Mean Titers (GMTs) to S-2P
Geometric Mean Response (95% CI)
Convalescent Sera (N=38) = 142,140 (81,543 – 247,768)
|N||25 μg||N||100 μg||N||250 μg|
|(72 – 187)||(65 – 266)||(81 – 392)|
|(18,723 – 55,587)||(56,403 – 132,016)||(102,155 – 261,520)|
|(29,094 – 55,621)||(79,050 – 150,874)||(128,832 – 353,896)|
|(267,402 – 571,780)||(606,247 – 1,007,156)||(973,972 – 1,635,140)|
|(281,597 – 512,152)||(656,336 – 1,002,404)||(806,189 – 1,227,115)|
|(206,071 – 436,020)||(619,310 – 989,244)||(924,878 – 1,536,669)|
|* All participants seroconverted at Day 15|
|Table 2: Live Virus Neutralization Assay PRNT80 Geometric Mean Results|
|Geometric Mean Response (95% CI)|
|Convalescent Sera (N=3) = 158.3|
|N||25 µg||N||100 µg|
(184.0 – 627.1)
(460.1 – 930.5)
|* All Day 1 specimens exhibited less than 80% inhibitory activity at the lowest dilution tested, 1:8, and so were assigned a titer of 4|
|Table 3: Pseudovirus Neutralization Assay ID50 Geometric Mean Results|
|Geometric Mean Response (95% CI)|
|Convalescent Sera (N=38) = 109.2 (59.6 – 199.9)|
|N||25 µg||N||100 µg||N||250 µg|
(9.8 – 21.4)
(13.3 – 42.3)
(14.1 – 48.3)
(9.7 – 14.1)
(12.1 – 27.4)
(13.3 – 32.3)
(69.8 – 160.4)
(182.0 – 361.1)
(308.6 – 452.2)
(71.2 – 177.1)
(261.2 – 452.7)
(266.3 – 414.5)
(51.0 – 127.6)
(163.2 – 329.3)
(221.0 – 330.3)
|* All participants seroconverted at Day 15|
Samples that do not neutralize at the 50% level are expressed as <20 and plotted at half that dilution, i.e., 10