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Vaccine Data From Novavax

Several days after making some headlines with a press release about the data, the Novavax vaccine effort has published on Medrxiv. The is the first look at human data we have at an approach using recombinant coronavirus proteins (plus an adjuvant, in this case a proprietary saponin natural product). The protein itself is produced in the good ol’ Sf9/ baculovirus cell expression system, a real workhorse over the years for recombinant proteins. I’m glad to see this one, because we need as many different techniques as we can get. So how well does it work?

This was done in 131 adults, with two injections three weeks apart. These were either 5 micrograms or 25 micrograms of protein, with and without the company’s proprietary adjuvant. As seen in some of the other trials, there were six patients in a “sentinal” group who underwent the first dosing with observation before the rest of the groups were vaccinated (five groups, 25/group, with a placebo cohort). The antigen itself is the full-length Spike protein, with the furin protease site mutated and two proline substitutions introduced to stabilize the conformation. That’s pretty much the protein that the J&J vaccine is causing cells to produce via its adenovirus vector, so in this case it’s just being injected directly.

The reactions to the vaccine itself look fine – the usual soreness at the injection point, and a couple of reports of mild transient fever. These were more noticeable in the adjuvant group, which basically tells you that the adjuvant is probably just doing its immunogenic thing. Overall, there seem to be no overt safety signs to cause any concern.

And indeed, the adjuvant does really help a great deal. At Day 21 (before the second injection), antibody levels against the Spike protein antigen were tenfold higher in the adjuvant group as opposed to the plain injections. The response was also stronger after the second injection, and by 14 days after that one (Day 35 overall) the antibody levels for the adjuvant groups were at least 100x over the non-adjuvant ones. So that settles that! Interestingly, the levels were quite similar for the 5 microgram and 25 microgram groups, so that should help with overall vaccine manufacturing as well.

The effect on neutralizing antibodies was even more striking – it’s adjuvant or bust when measured that way (which is really the key figure, anyway). After the second vaccination, the preprint reports that neutralizing antibodies were 4x those seen in convalescent serum of outpatient-treated coronavirus cases, and spanning the same range as hospitalized convalescent cases. 16 patients were selected at random from the treatment groups to check T-cell response, and these showed CD4+ cells that were heavily biased towards Th1. We don’t know how long either response lasts – this paper covers out to two weeks past the second dose, but you can be sure that these numbers are being collected.

These look like strong results, and I’m glad that this candidate is in human efficacy trials. That’s something to emphasize – we’re all (naturally enough) trying to make what calls we can based on the Phase I immunogenicity data and the non-human-primate challenge experiments. But what matters is real human data from out in the field via the Phase II/III clinical trials. Right now, we have several vaccines that look like they will have good chances of working (this one very much among them). And we’re going to sort them out the only way that they can be sorted.

103 comments on “Vaccine Data From Novavax”

  1. Ted says:

    Nice summary. Some have called it “best in class” however it has yet to start phase 2/3. Also how quickly can this be scaled up for distribution? It seems to me that in this race “first in class” is critical.

    1. JasonP says:

      From the Comanpany’s website:

      >>>>In June 2020, we were awarded a contract by the U.S. Department of Defense under which we receive funding of up to $70 million for the manufacturing of NVX-CoV2373. In May 2020, we announced that the Coalition for Epidemic Preparedness Innovations (CEPI) will invest up to $384 million of additional funding, on top of $4 million it invested in March, to advance clinical development of NVX-CoV2373.

      In July 2020, we were selected to participate in Operation Warp Speed (OWS), a U.S. government sponsored program that aims to begin delivering millions of doses of a safe, effective vaccine for COVID-19 in 2021, under which we receive funding of $1.6 billion. We will demonstrate we can rapidly stand up large-scale manufacturing and transition into ongoing production, including the capability to stockpile and distribute large quantities of NVX-CoV2373 when needed. OWS funds the late-stage clinical studies necessary to determine the safety and efficacy of NVX-CoV2373, including a pivotal Phase 3 clinical trial with up to 30,000 subjects beginning in the fall of 2020. OWS funding supports our plans to file submissions for licensure with the FDA.<<<<
      https://novavax.com/our-pipeline#nvx-cov2373

      And overseas:
      (Reuters) – Novavax Inc said on Wednesday it has entered a supply and license agreement with the Serum Institute of India for the development and commercialization of its COVID-19 vaccine candidate.

      The Indian drugmaker will have exclusive rights for the vaccine in India during the term of the deal and non-exclusive rights during the “Pandemic Period” in all countries other than those designated by the World Bank as upper-middle or high-income countries.

      The deal was signed on July 30, according to an SEC filing by Novavax. https://bit.ly/3iggGQv
      https://finance.yahoo.com/news/novavax-signs-covid-19-vaccine-225839980.html

    2. Searching4alpha says:

      Mfg has already begun in several locations including at Emergent Biosolutions, Fujifilm Diosynth in Texas and Serum Institute India (largest vaccine manufacturer in the world). Novavax will have its new facility in Praha producing by Sept/Oct. 100M doses due to OWS by early January, and on Tues company indicated they would be able to do between 1B and 2B doses (vaccination of 500M – 1B people) in 2021. The production range uncertainty is due to not yet fully defining the final dose ranges for all adult age groups. They will likely explore a lower dose, I anticipate 2.5 or 3ug, along with just reported 5ug dose in 18-59 yr age range as well as a higher dose in elderly population to counter immune senescence. Phase 3 Flu vaccine trial completed by NVAX in March, using the same vaccine production and adjuvant system, gave market beating results in all age groups, including elderly. Given the phase 1 Covid results I anticipate this to translate to Covid protection in elderly.

      1. DM says:

        There’s absolutely no way a vaccine could have gone through full safety testing and development already and be ready for manufacturing and dissemination!

        Man, the gullible leading the blind leading the gullible!

        1. Tim Bergel says:

          I think the article makes it clear that this vaccine has not gone through full testing – like a number of other firms (J&J I know of) they are investing in and developing manufacturing capacity before the vaccine is known to be effective. A big bet, and a worthwhile one too if it shaves a few months off the time until availability.

        2. Mammalian scale-up person says:

          It hasn’t. Most vaccine developers are currently using contract manufacturers specifically so they do not have to build their own facilities at-risk. It’s a pretty common thing to do for most drugs, I think: building your own manufacturing facility takes 2-3 years minimum if you already have real estate, permitting figured out, and preferably shell space + utilities secured, so if you are building your own, you are forced to start construction well before Phase 3 is anywhere near complete. This is a fairly large investment even for the Mercks and Pfizers of the world, and they’d rather give the risk to someone else who already has a facility constructed that can be used with only minor changes.

          By the time manufacturing is brought back in-house, a contract manufacturer has already been making batches for nearly 10 years and they are fairly certain of the capacity required. That’s another huge risk, wrongly estimating demand – what happens if you build a facility and then find out demand is such that you needed a 2X larger facility? If you did site selection based on “we will only ever need to make 50 million doses per year,” and it turns out you need the water, waste treatment and logistics for 100 million doses per year and those things are simply unavailable at the chosen site – you now have to pay for a lot of new construction and several years more delays finding a new site and building it out. Better to wait for your Phase IV studies and patient population estimates to pan out, before you bring that risk on yourself.

    3. Buzz says:

      Why would being first be better if the vaccine is clearly inferior? This is baffling logic. Some of the first generation vaccines may also not have durable immunity and are unproven platforms that have never been scaled up

      1. Ted says:

        Being first approved would mean that a vaccine would have been demonstrated as efficacious and safe in phase 3. If that happens in late fall 2020, do you think people would not take that first vaccine and just wait for the results of Novavax vaccine from the phase 3 which would just be starting in the fall?

        1. David G Whiteis says:

          I might be tempted to do just that. But this does bring up an interesting question: On the one hand, we’ll need more than one successful vaccine in order to produce enough doses to meet the world’s needs (almost 8 billion people — meaning almost 16 billion doses if the approved vaccine requires two shots. And that doesn’t even begin to bring subsequent booster shots into the equation.) On the other hand, it’s likely that if several vaccines meet approval, some will be more effective and/or more long-lasting than the others. So — who gets which? Do we scrap everything except the unquestioned “leader” in terms of effectiveness, basically going back to the drawing board again? Do we ration the vaccines? If so, how do we do that?

          If we’re fortunate enough to get several equally effective vaccines approved, people will still be confused as to which one they “should” take. Will the companies start advertising their vaccines to introduce ‘marketplace competition” into the game? How, in other words, will mutiple approved vaccines be dealt with in terms of policy? (And what if another, much more effective one, makes its debut five or six month after that? Will the people who took the earlier vaccine want, or be able, to take the new, better one when it gets introduced? Or will this be a “one to a customer” situation, leaving the “early” customers at hgher risk than the ones who waited a little bit longer?)

          1. David G Whiteis says:

            . . ,. and, of course, a lot of this depends on how free we’ll be to choose our vacccine in the first place. If you go to your regular physician to be vaccinated, or to your local neighborhood health clinic, you’ll have to take what they give you. How much “comparison shopping” will most people, realistically, be able to do?

  2. steve says:

    As Charley Janeway said, adjuvants are the dirty secret of immunology. Polly Matzinger’s danger theory posits that the immune system didn’t evolve to sense “self” it evolved to sense danger. Unless there is a signal that alerts the innate immune system to danger then the system avoids going into hyperdrive in order to avoid toxicity. Adding an adjuvant provides the danger signal (Toll receptor or other) and activates potent immune responses.

    1. loupgarous says:

      How often has a vaccine using an adjuvant to provoke an immune response failed to provde a useful immune response to the targeted organism? Just asking.

    2. Sc says:

      This always concerns me a little. I got an allergy to red meat (or more specifically to alpha galactose found in other mammals’ cells) from a tick bite, apparently from the combination of remnant animal blood and highly immunogenic bug enzymes. I assume that generating an allergic response wouldn’t be possible with this type of adjuvant but the thought makes me a bit itchy.

  3. I’m very happy to see these data, even though they are behind others. While this is behind the more teched-up vaccines, such as the RNA vaccines which have shown such promise, I can’t help thinking that its similarity to vaccines that people are used to, will help this win out unless its hopeless.

    1. loupgarous says:

      Is a “belt and suspenders” approach (say, this vaccine because its approach will give some traditional coverage plus a recombinant vaccine more likely to give robust memory T cell coverage) something we ought to be considering? Or is ADE an issue that way?

  4. gippgig says:

    Off topic but likely to be of interest:
    The activities of drug inactive ingredients on biological targets
    Science Vol. 369 issue 6502 p. 403 doi: 10.1126/science.aaz9906

  5. x says:

    Derek, any follow-up coming on the vaxxine russians are going to start using now?

  6. Matthew says:

    Derek,
    When (in the trials) and how would any ADE be observed in the cohort? Or are the trials not lengthy enough to discover this phenomenon?

    1. Just another chemist says:

      It is most likely that antibody dependent enhancement will be seen/not seen during phase 2/3, due to the length and larger patient population. I would also expect that if ADE is seen in any COVID-19 vaccine clinical trial it will be scrutinized more closely in all of them

    2. Calvin says:

      This is the trickiest of tricky asks. ADE for the Dengue vaccine did not sow up until about 2 years after immunization. In the real world there is a little more variation, but it is not always immediate. So for all of these vaccines, ADE is a risk that is unbelievably hard to assess. The preclinical models are not really predictive of patients. Plus there is not real agreement on what the hell is going on. See https://www.nature.com/articles/s41586-020-2538-8. So all I think I can say, is cross your fingers…

  7. Franknbeans says:

    The convalescent serum came from multiple subgroups including hospitalized patients, not just outpatients. Also, they used 99% neutralization. Combined with full sterilizing immunity in macaques, this is indeed, a very, very good result.

    1. Matthew says:

      How helpful or effective has convalescent serum performed as a therapy?

      1. Marko says:

        A recent meta analysis of observational studies suggested ~50% reduction in mortality. No RCT data yet , though , so this could end up being a hydroxychloroquine rerun. Hopefully we’ll get some data out of the Recovery trial soon.

  8. TallDave says:

    exciting to see so many vaccines in efficacy trials

  9. Ben says:

    There is nothing in the report about CD8+. Should that worry us?

    1. dwh says:

      Recombinant subunit vaccines do not typically to elicit strong CD8+ T-cell responses, so this is not an unexpected result (although sometimes a strong adjuvant can lead to some cell mediated immunity). Obviously, from an efficacy standpoint one would like to have the broadest array of effectors possible, but if the vaccine generates high level, sustained neutralizing antibody responses and the target antigen is relatively stable from a mutational perspective, then there is precedence that antibody responses alone are sufficient.

      From the data, the biggest issue for this candidate is that it appears that the adjuvant, which has not been widely used in previous mass vaccination campaigns (compared to the more conventional ones like alum) is an absolute requirement for immunogenicity. If safety signals to the adjuvant start being detected even in a relatively modest percentage of recipients, that will pose a significant challenge for broad rollout.

  10. Nate says:

    INO had better titers at a 4 month post vac inoculation in the challenge.
    Also zero AEs.
    Why is nobody talking about there Vaccine. Based on actual peer review (not preprint), the safety profile, the 95% b and t in p1, the very telling move to a p2/p3 in only front line med and first responders, and the GMP certified mfg it would seem they are the closest of any of the candidates to an EUA.
    Was everyone given a gag order on ino or what?

    1. Searching4alpha says:

      This is completely incorrect. Your confusing total antibody number, which includes both non-effective and effective (known as neutralizing antibodies), with neutralizing antibodies which are all that matter. DNA (innovio) and mRNA approaches both produce ver high numbers of ineffective antibodies, but much lower levels than NVAX vaccine when it comes to neutralizing antibodies, which are what counts. It’s even worse than this because NVAX used a 100% neutralizing level in its testing but the mRNA folks are using a 50% neutralizing criteria. NVAX also used human convalescent serum derived from sicker people as the criteria to judge against, and they still reported a greater multiple of neutralizing antibody levels than either the DNA or mRNA approaches. Bottom line is DNA and mRNA approaches are a bit faster but they produce a less effective vaccine. This will become completely, irrefutably clear through the OWS phase 3 process, where for the first time in history we’ll see multiple vaccines run through the same clinical trial network, managed by the same Independant (not company affiliated) people, using identical criteria and measures of performance measured in one centralized laboratory at NIH. The power of this trial structure to ensure that only safe and effective vaccines make it to market through this system isn’t yet clear to the public, but hopefully it will be made so.

      1. Nate says:

        Produced a greater level at what time frame?
        INO measured at 12 weeks and the spike specific t were higher than at week 1 post vacc.
        Not trying to get territorial here but it seems we’re comparing apples to oranges. INO measured at 12 weeks and saw indications of immune memory.
        Again zero grade 1 or above AEs (so far the only candidate I know of)
        95% b and t in the lower tract from the p1 prelim data (so far the only candidate I know of)
        And immune memory after 4 months in the challenge (not aware of anyone else who took it to 4 months to inoculate)

        Again not trying to diminish Nvax in any way but the ino results seem to be leading the pack based on what’s publicly available.
        Can’t wait to see side by side in the same lab.

        1. KC says:

          Nate, Novavax has better business and political relationships. This seemed to be indicated in a recent article published to the NY Times. You are correct in your assessment in response to Searching4Alpha.

          His assertion that DNA is a “less effective vaccine” doesn’t have a factual basis. We don’t know what level of neutralizing antibodies are required to prevent infection and disease. Also, we don’t have a pre-print of INO’s Phase 1 data to judge if they use convalescent serum derived from hospitalized patients. Like you said, INO is the only candidate to have peer-reviewed preclinical results and are publishing peer-reviewed Phase I data.

          Also, as mentioned, INO is the only candidate to test at least medium-term immunity, and they were confident in doing so. All of these other candidates started trials early, if not earlier than INO, and had just as much opportunity to test whether their candidate prevented infection and/or disease more than 4-6 weeks after. I believe INO’s challenge was 4 months.

          Another point is that Phase I is primarily about safety, and INO’s vaccine is hands-down the safest, along with the fact that directly comparing GMTs is apples to oranges since each candidate uses different assays and perhaps inoculation periods.

        2. dwh says:

          We have essentially no clinical immunogenicity data from Inovio, so it is hard to say exactly where INO-4800 fits in the hierarchy of candidates. The quote from the press release characterizing the immunogenicity results is very vague: “Analyses to date have shown that 94% (34 out of 36 total trial participants) demonstrated overall immunological response rates based on preliminary data assessing humoral (binding and neutralizing) and T cell immune responses.”

          Based on how they presented their MERs data, my guess is that the 94% of subjects is the number that had detectable antibody or T-cell response for at least one time point after immunization. The issue with their MERs data is that, when the neutralizing antibodies were induced in ~60-90% of subjects (depending on the study), they were low in magnitude and transient in duration. Based on the data from the SARS-CoV-2 challenge study in NHP where they were not able to prevent infection (just mitigate the severity) with even a modest viral challenge dose, I am afraid that the SARS-CoV-2 data will look similar. That being said, it is in their favor that their challenge study does have the longest interval between immunization and challenge. The biggest issue with DNA vaccines has always been their potency and it does not look like the immunogenicity of the native SARs-CoV-2 spike protein is strong enough to overcome that. Inovio also did not do any antigen optimization, such as the proline substitutions to enhance conformational stability, which, based on the groups that are testing multiple antigen forms, looks like it will be important. While they can make the case that T-cells will prove capable of providing protection in the absence of neutralizing antibodies, they should have included the nucleocapsid in the vaccine because it is not clear that the spike has enough good T-cell epitopes when considering HLA diversity.

          Bottom line is that when you combine the track record of DNA vaccines, the need for a special delivery device, the data from the MERS program, the INO4800 antigen design, and the early returns from the SARS-CoV-2 data, there are certainly reasons for concern.

          Of course I am happy to be proven wrong and see another promising candidate advancing into later stage development.

          1. KC says:

            Sterilizing immunity is not the goal though, long-term immunity in reducing the severity of disease and safety is the goal. Almost no vaccines provide sterilizing immunity and COVID vaccines, if they even work to reduce disease, will be no different. We know from convalescent patients that antibodies wane in a matter of weeks and months. T-Cell immunity is the saving grace, so I’m not sure why people are not more concerned about a lack of T-Cells and no challenge models outside the range of short-term immunity (literally 4-6 weeks for some of these candidates other than Inovio).

          2. dwh says:

            @KC While not the sine qua non for an approvable vaccine, sterilizing immunity is the obviously the goal. Does it mean that Janssen is correct in prioritizing antibody responses in their candidate down selection criteria? Not necessarily. Are T-cells important? – Clearly, yes, but if that was Inovio’s strategy they should have designed their vaccine much differently.

            Regardless, a Phase III vaccine study designed to show a reduction of disease severity as a primary outcome measure as opposed to a reduction in infection incidence will be a serious, if not impossible, challenge in the short term, especially for a pathogen that has as widely varying disease severity as SARS-CoV-2.

            The cold hard reality of clinical trial design is that infectious disease vaccine efficacy studies are currently built around demonstrating a reduction in infection frequency. Proving a reduction in disease severity is much trickier. Candidates that do not prevent SARS-CoV-2 infection in a significant fraction of recipients will have a huge challenge in finding a short term path to proving efficacy in a prophylactic mass vaccination setting. While safety is obviously of critical importance how do you perform a risk benefit analysis against other candidates if you cannot demonstrate efficacy?

            Regarding Inovio’s challenge study, I give them credit for pushing the envelope on challenge interval, but the reality is that they did 2 immunizations at the human vaccine dose to ~5 kg non-human primates and followed 13 weeks later by a relatively low challenge dose and still had evidence of replicating virus in the nasal passage of all vaccinated animals.

            The reality is the data we have access to for INO-4800 is just not that good and nothing the their previous work with MERs and other pathogens provides optimism that the clinical data will compete with the other leading candidates out there.

          3. Phil says:

            dwh, thanks for your thoughtful posts, you’re clearly well informed.

            KC and Nate, we’ve clearly raised for you the key issues you should be focusing on. What you do with this information is now up to you.

            NVAX has now shown sterilizing immunity in NHP’s, an excellent safety profile (similar AE’s to a typical flu shot), very high levels of neutralizing antibodies and the desired cellular response profile…all at a dose level of only 5ug of antigen, which is critical to ensuring that very large dose numbers can be made rapidly available. Their mfg process is well understood and rapidly scalable, and importantly the vaccine is easily administered and highly stable requiring only refrigeration, unlike other vaccine technologies. Innovio on the other hand has clearly inferior immunogenicity data and doesn’t even have a scalable working delivery device!! I encourage you to look more carefully at both the data and the manufacturability of the Innovio product. If you do this, I believe you will find, as I have, that the innovio product is unlikely to play any significant commercial role in this pandemic.

          4. Dorean says:

            Just in case you need an update on INOVIO’s P1 complete results.

            INOVIO’s COVID-19 DNA Vaccine INO-4800 Provides Protection with Memory Immune Responses In Non-Human Primates Challenged with SARS-CoV-2 Virus
            July 30, 2020
            DownloadPDF Format (opens in new window)
            – INO-4800 showed durable antibody and T cell responses in rhesus macaques for 4 months
            – INO-4800 is the only vaccine to demonstrate long-term protection in non-human primates challenged with SARS-CoV-2 virus 13 weeks from vaccination
            – Memory T and B cell responses resulted in reduced viral loads and faster viral clearance in macaques’ lungs and nasal passages
            – INO-4800 vaccination generated antibodies neutralizing both the earlier strain of virus as well as the mutant variant (D614G) that has emerged with greater infectivity, and now accounts for >80% of newly circulating virus
            – No antibody-dependent enhanced disease events were reported

            PLYMOUTH MEETING, Pa., July 30, 2020 /PRNewswire/ — INOVIO (NASDAQ:INO), a biotechnology company focused on rapidly bringing to market precisely designed DNA medicines to treat and protect people from infectious diseases and cancer, today announced that its COVID-19 DNA vaccine INO-4800 targeting SARS-CoV-2 was effective in protecting non-human primates (NHPs; specifically rhesus macaques) from live virus challenge 13 weeks after the last vaccination. These protective results were mediated by memory T and B cell immune responses from INO-4800 vaccination.

            These results, submitted to a peer-reviewed journal and also published today on the non-peer reviewed online preprint site bioRxiv, demonstrate that INO-4800 reduced viral load in both the lower lungs and nasal passages in macaques that received two doses of INO-4800 (1 mg) four weeks apart and then were challenged with live virus 13 weeks after the second dose (study week 17). The reduced viral loads following exposure to SARS-CoV-2 infection at this timeframe demonstrate an important durable impact mediated by INO-4800. This is the first time a vaccine protection in non-human primates was reported from memory immune responses as previously reported monkey vaccine challenge studies were conducted at the time near their peak immune responses (1-4 weeks from their last vaccination).

            INO-4800-treated animals demonstrated seroconversion after a single vaccination, with protective neutralizing antibodies and T cells lasting in their blood more than four months after the initial dose. The antibody levels were similar to or greater than those seen in patients who have recovered from COVID-19, the infection caused by SARS-CoV-2, and the T cell responses were significantly higher than those from convalescent patients.

            Dr. J. Joseph Kim, President and Chief Executive Officer of INOVIO, said, “All other previously reported NHP vaccine protection studies actually challenged the animals at the peak of their immune response. Our study demonstrates that INO-4800 could provide protection in a more real-world setting, where vaccine-generated memory immune responses protected NHPs for more than 3 months (13 weeks) from the last vaccination. Given the importance of protective antibody and T cell responses, this study gives us more confidence as we continue to advance INO-4800 in the clinic. We believe INO-4800 holds significant potential to help address this global public health crisis.”

            B cells are responsible for producing the antibodies that recognize SARS-CoV-2, while T cells play a role in killing the virally infected cells as well as supporting the B cell response. The published data support that immunization with INO-4800 limits active viral replication and has the potential to reduce severity of disease, as well as reduced viral shedding in the nasal cavity. In the study, researchers assessed the ability of INO-4800 to induce acute and memory T cell and B cell immune responses, including neutralizing antibody responses against both early virus as well as now-dominant G614 mutant variants. To INOVIO’s knowledge, this is the first report of vaccine-induced responses driving immunity against G614 variants. A strong anamnestic or memory T and B cell responses were demonstrated following challenge with the live virus.

            “As we eagerly anticipate initiating a Phase 2/3 efficacy trials this summer, an animal challenge is currently the closest thing we have to testing a vaccine’s efficacy when confronting a live virus. We are very encouraged with the duration of protection that INO-4800 demonstrated in this NHP study and look forward to reassessing its impact on durability of response at 12 months out from our other ongoing non-human primate and animal challenge studies,” said Dr. Kate Broderick, Ph.D., INOVIO’s Senior Vice President, Research & Development.

            “In addition to safety and efficacy, it is essential that any vaccine targeting SARS-CoV-2 generates a relevant durability of response,” Dr. Broderick added. “A vaccine that only provides protection for a very short period of time is not going to realistically solve the problem of this pandemic.”

            A separate NHP study evaluating the durability of INO-4800 at 12 months after vaccination is currently under way. INO-4800 also has been selected by U.S. Operation Warp Speed for its COVID-19 non-human primate challenge study.

            In May, the peer-reviewed journal Nature Communications published an INOVIO study (“Immunogenicity of a DNA vaccine candidate for COVID-19”) showing that vaccination with INO-4800 generated robust binding and neutralizing antibody and T cell responses in mice and guinea pigs. The study was funded by a grant from the Coalition for Epidemic Preparedness Innovations (CEPI).

            About INO-4800

            INO-4800 is INOVIO’s DNA vaccine candidate created to protect against the novel coronavirus SARS-CoV-2, which causes COVID-19. INO-4800 is currently in Phase 1 trials in the U.S. and a Phase 2/3 trial is planned for the summer. Interim Phase 1 results showed a favorable safety profile and strong immunogenicity, including antibody and T cell responses. The Phase 1 study recently expanded to include adults over the age of 65 with no age limit given the propensity for COVID-19 to severely impact the health of older people. INO-4800 also is in Phase 1/2 trials for COVID-19 in South Korea and China.

            In animal studies, INO-4800 has demonstrated robust and durable T cell and B cell acute and memory responses in a non-human primate challenge study showing protective immune responses in both nasal passages and lungs. INO-4800 also was selected by U.S. Operation Warp Speed for its COVID-19 non-human primate challenge study.

            INO-4800 was designed using INOVIO’s proprietary DNA medicine platform rapidly after the publication of the genetic sequence of SARS-CoV-2. INOVIO has extensive experience working with coronaviruses and is the only company with a Phase 2 vaccine for a related coronavirus that causes Middle East Respiratory Syndrome (MERS).

            INO-4800 is the only nucleic-acid based vaccine that is stable at room temperature for more than a year and does not need to be frozen in transport of storage, which are important factors when implementing mass immunizations.

            About INOVIO’s DNA Medicines Platform

            INOVIO has 15 DNA medicine clinical programs currently in development focused on HPV-associated diseases, cancer, and infectious diseases, including coronaviruses associated with MERS and COVID-19 diseases being developed under grants from the Coalition for Epidemic Preparedness Innovations (CEPI) and the U.S. Department of Defense. DNA medicines are composed of optimized DNA plasmids, which are small circles of double-stranded DNA that are synthesized or reorganized by a computer sequencing technology and designed to produce a specific immune response in the body.

            INOVIO’s DNA medicines deliver optimized plasmids directly into cells intramuscularly or intradermally using INOVIO’s proprietary hand-held smart device called CELLECTRA®. The CELLECTRA device uses a brief electrical pulse to reversibly open small pores in the cell to allow the plasmids to enter, overcoming a key limitation of other DNA and other nucleic acid approaches, such as mRNA. Once inside the cell, the DNA plasmids enable the cell to produce the targeted antigen. The antigen is processed naturally in the cell and triggers the desired T cell and antibody-mediated immune responses. Administration with the CELLECTRA device ensures that the DNA medicine is efficiently delivered directly into the body’s cells, where it can go to work to drive an immune response. INOVIO’s DNA medicines do not interfere with or change in any way an individual’s own DNA. The advantages of INOVIO’s DNA medicine platform are how fast DNA medicines can be designed and manufactured; the stability of the products, which do not require freezing in storage and transport; and the robust immune response, safety profile, and tolerability that have been demonstrated in clinical trials.

            With more than 2,000 patients receiving INOVIO investigational DNA medicines in more than 7,000 applications across a range of clinical trials, INOVIO has a strong track record of rapidly generating DNA medicine candidates with potential to meet urgent global health needs.

            About INOVIO

            INOVIO is a biotechnology company focused on rapidly bringing to market precisely designed DNA medicines to treat and protect people from infectious diseases, cancer, and diseases associated with HPV. INOVIO is the first and only company to have clinically demonstrated that a DNA medicine can be delivered directly into cells in the body via a proprietary smart device to produce a robust and tolerable immune response. Specifically, INOVIO’s lead candidate VGX-3100, currently in Phase 3 trials for precancerous cervical dysplasia, destroyed and cleared high-risk HPV 16 and 18 in a Phase 2b clinical trial. High-risk HPV is responsible for 70% of cervical cancer, 91% of anal cancer, and 69% of vulvar cancer. Also in development are programs targeting HPV-related cancers and a rare HPV-related disease, recurrent respiratory papillomatosis (RRP); non-HPV-related cancers glioblastoma multiforme (GBM) and prostate cancer; as well as externally funded infectious disease DNA vaccine development programs in Zika, Lassa fever, Ebola, HIV, and coronaviruses associated with MERS and COVID-19 diseases. Partners and collaborators include Advaccine, ApolloBio Corporation, AstraZeneca, The Bill & Melinda Gates Foundation, Coalition for Epidemic Preparedness Innovations (CEPI), Defense Advanced Research Projects Agency (DARPA)/Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND)/Department of Defense (DOD), GeneOne Life Science/VGXI, HIV Vaccines Trial Network, International Vaccine Institute (IVI), Medical CBRN Defense Consortium (MCDC), National Cancer Institute, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Ology Bioservices, the Parker Institute for Cancer Immunotherapy, Plumbline Life Sciences, Regeneron, Richter-Helm BioLogics, Roche/Genentech, University of Pennsylvania, Walter Reed Army Institute of Research, and The Wistar Institute. INOVIO also is a proud recipient of 2020 Women on Boards “W” designation recognizing companies with more than 20% women on their board of directors. For more information, visit http://www.inovio.com.

            CONTACTS:
            Media: Jeff Richardson, 267-440-4211, jrichardson@inovio.com
            Investors: Ben Matone, 484-362-0076, ben.matone@inovio.com

            This press release contains certain forward-looking statements relating to our business, including our plans to develop DNA medicines, our expectations regarding our research and development programs, including the planned initiation and conduct of preclinical studies and clinical trials, and the availability and timing of data from those studies and trials. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials, product development programs and commercialization activities and outcomes, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA medicines, our ability to support our pipeline of DNA medicine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by us or our collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that we and our collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide us with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether we can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of our technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2019, our Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 and other filings we make from time to time with the Securities and Exchange Commission. There can be no assurance that any product candidate in our pipeline will be successfully developed, manufactured or commercialized, that final results of clinical trials will be supportive of regulatory approvals required to market products, or that any of the forward-looking information provided herein will be proven accurate. Forward-looking statements speak only as of the date of this release, and we undertake no obligation to update or revise these statements, except as may be required by law.

            Cision View original content:http://www.prnewswire.com/news-releases/inovios-covid-19-dna-vaccine-ino-4800-provides-protection-with-memory-immune-responses-in-non-human-primates-challenged-with-sars-cov-2-virus-301103039.html

            SOURCE INOVIO Pharmaceuticals, Inc.

          5. Lambchops says:

            @ Dorean

            If you’re going to text dump a press release it helps if you at least understand what it is (or read it in the first place!

            Last time I checked preclinical results in primates aren’t “P1 results”. The press release even says phase I trials are ongoing.

  11. peter waldo says:

    Does anyone else get the feeling that the promising but almost entirely untested mRNA therapies will be hastily approved (favored?) vs. recombinant therapies or a “traditional” vaccines like this one? With potential myriad mRNA side effect risks lurking how is it that there is not more concern and caution being voiced by everyone?

    1. Thomas says:

      I don’t have that feeling. Also, mRNA might be safer than a modified and non-viable virus based vaccin, which will contain much more mRNA than just the antigen part that is in the mRNA vaccine.

      1. peter waldo says:

        That’s true, we’ll get the data pretty soon if the potential timelines mentioned hold

  12. Jeff W says:

    “…there were six patients in a ‘sentinal’ group…”

    Do you mean “sentinel”?

    1. KazooChemist says:

      Quoting someone I cannot recall and only getting the gist of it correct, not the precise quote, “it is a sign on intelligence to know more than one way to spell a word”. I could Google this, but why bother.

      For some unknown and bizarre reason this brought back a memory from over fifty years ago. I was a high school senior and had just received a college scholarship (more details available for those with morbid interest). The local (Syracuse, NY) paper ran a story about it. At the time I was a garage band rock and roll star in a group with five other guys. The story claimed that I was in a sex member band. Boy did that pi$$ my mother off! Just another example of a vowel exchange gone awry.

      1. loupgarous says:

        Quote Investigator finds four possible sources for the quote or something like it: Mark Twain, Nyrum Reynolds, Hiram Runnels and Andrew Jackson.

        I’ve always heard it attributed to Mark Twain

        :”I never had any large respect for good spelling. That is my feeling yet. Before the spelling-book came with its arbitrary forms, men unconsciously revealed shades of their characters and also added enlightening shades of expression to what they wrote by their spelling, and so it is possible that the spelling-book has been a doubtful benevolence to us”

        or Andrew Jackson.

        “The variety of ways in which Groton Town-Clerks contrived to spell the same office is marvellous to behold. Evidently, like General Jackson, they despised a man who could spell a word in only one way.”

        The attribution to President Jackson sounds typical of him, but comes years after he died.

        For concision, then we can say “Andrew Jackson said “I despise a man who can think of only one way to spell a word.”, or if we have the time and want to impress our readers, quote Twain. It’s the 21st century, and soon no matter who we choose will be lost to an education system who damns them both for political incorrectness.

        1. Some idiot says:

          I like the classics, especially the wisdom of Winnie the Pooh:
          (something like)

          “I have wobbly spelling. It is good spelling, but the letters wobble into the wrong places.”

          Possibly foreseeing auto-correct incorrectly correcting?

          🙂

          1. A Nonny Mouse says:

            From one of the greats:

            “I’m playing all the right notes. But not necessarily in the right order.”

      2. Some idiot says:

        Try moving to a country that has three extra vowels in the language…! When I moved to Denmark, I tried to get up to speed as quickly as possible. They have ø, æ and å in their alphabet. Longer story, but the short version is this: there are plenty of words where if you accidentally swap the ø out with an o, you get a word with a completely utterly different meaning. Which is only accentuated when you sing with a choir and have a powerful voice.

        Says one with (quite red-faced) experience…

        🙂

    2. Jeff W says:

      “Enlightened shades of expression,” the “wobbliness” of letters and all that acknowledged and appreciated, it’s actually the quotation marks around the word that threw me off, as if that spelling was being transcribed precisely and intentionally. That’s what prompted the question.

  13. Klagenfurt says:

    Uh, what’s up with the demographics in this study? Only 2/132 black participants from a company in a state that’s 30% African American?

    1. Mike says:

      African Americans don’t have a lot of trust in clinical trials based on past incidents like the Tuskegee syphilis experiment. That makes recruitment difficult.

      Can’t say I blame them for the lack of trust.

      1. David G Whiteis says:

        This is an extremely important consideration. I believe that respected members of the community, both local –ministers, political leaders, educators — and national — public figures like Barack and Michelle Obama; public intellectuals such asTa-Nehisi Coates; respected individuals from popular culture (the hip-hop community, for instance, can do a lot of good in encouraging younger people to participate) — will need to step up and work hard to spread the word.

        1. David G Whiteis says:

          . . . and just to clarify, my comment had to do with willingness to take the vaccine once it’s been approved and introduced, not just willingness to participate in the clinical trials. The “racial” disparity here is pretty wide, also.

  14. Etienne Gomme says:

    Some very insightful dialogue here, thank you.

    Question: When measuring time to market, there are two variables.
    1. How long does it take to run a p3 trial?
    2. How long does it take to manufacture the vaccine?

    While NVAX may be slightly behind in the trial process, could an argument be made that their manufacturing process is faster.

    NET – NVAX may be ready for distribution before any of the competitors but behind in the approval process. True?

    If true, is it possible that governments, FDA and others may accelerate p3 data collection and analysis for the NVAX product?

    1. loupgarous says:

      Almost everyone in the SARS_CoV2 vaccine sweepstakes has committed to some degree to at-risk manufacturing – so they’re all going to be at least at pilot plant stage, churning out enough to evaluate various dosages in various study arms (in this case, two injections per patient, so find out how many patients will be getting study drug in each trial, at what dosage, and you know how much of each vaccine is being made (plus some extra for compassionate use and ‘wastage’).

      The other question’s harder to answer, each vaccine’s got a different manufacturing procedure.

  15. EJ says:

    All this Phase 1 data seems so positive.

    What happens when a Phase 1 trial fizzles, gets very mixed results, or fails spectacularly? Does the data usually get published?

    1. Derek Lowe says:

      They do when the spotlight is this bright, for sure.

  16. loupgarous says:

    Depends on how badly a P1 trial fizzles. The death in one healthy volunteer’s case (and brain damage of varying severity to other healthy volunteers) during the BIA 10-2474 trial in France and multi-system organ failures in the TGN1412 P1 study during a healthy volunteer trial in London pretty much assured the word would get out.

    If nothing else, the volunteers themselves are entitled to know what happened. Usually, if the drug trial sponsor doesn’t send a press release soon after a Phase 1 trial is stopped for toxicity, the regulatory agency concerned will.

  17. MTK says:

    Comparing the various vaccine approaches are there any that have a clear advantage or disadvantage in terms of actual distribution and use? I’m thinking about things like stability, storage conditions, mode of administration, etc.

    Or are those types of things still in the too early to tell stage?

    “First in class” or even “best in class” based on effectiveness may end up being secondary to most readily available.

  18. Luis says:

    The more available vaccines the quicker we can have enough supply to get to more people worldwide so this has to be good news and i wish that the decisive trials are successful

  19. David G Whiteis says:

    The use of the adjuvant is very encouraging. My primary concern, though, is that apprently this vaccine also requires at least two doses to be effective. Even distregarding the immense logistical problems this creates (e.g., manufacturing and distributing a minimum of two doses for every individual targeted, or upwards of 14 billion dose worldwide), will this really be feasible? People will have to schedule a follow-up appoinment in order for the vaccine to really work. Remember — things like “planning ahead” are, in reality, privileges that not all people have. Life for many of the world’s poor (including many in the U.S.) is a matter of day-to-day, even hour-to-hour, survival. (For that matter, even many people in relatively privileged circumstances often fail to honor follow-up appointments with their doctors.) What has been the track record for other vaccines and treatments that required a follow-up visiit within a relatively brief period of time. Has compliance been sufficient to ensure effectiveness?

  20. Simon Auclair the Great and Terrible says:

    Derek please a How Not to do it on ammonium nitrate storage.

    1. Geoff P says:

      “Derek please a How Not to do it on ammonium nitrate storage.”

      He already has, and the photograph from the 1920s of that ‘accident’ bears a remarkable similarity to the Beirut port blast :

      https://blogs.sciencemag.org/pipeline/archives/2017/03/03/how-not-to-do-it-breaking-up-ammonium-nitrate

      For those with little time, here’s the pic, all on its own :

      https://blogs.sciencemag.org/pipeline/wp-content/uploads/sites/2/2017/03/Oppau-768×576.jpg

      Derek’s categories (upper right of the main page) are well worth perusing, especially “Things I’m Glad I Don’t Do” and “Things I Won’t Work With”…

  21. Hólmsteinn Jónasson says:

    Early treatment with hydroxychloroquine: a country-randomized controlled trial. “As of August 6, 2020, countries using early HCQ are predicted to have a 79.1% lower death rate after adjustments.” ?https://hcqtrial.com/#setup

    1. Derek Lowe says:

      No. This is not a “country-randomized controlled trial”. That web site is disinformation and presents what appears to be a deliberately false picture of the HCQ situation.

      1. Still Driving says:

        This is the one site I’m familiar with that has no visible partisanship regarding HCQ. It seems the majority believes the virus understands politics in one particular country, and chooses to work or not based on which faction endorses it.

        The conflicting info about it is genuinely confusing; there appear to be a few studies showing that it works, more showing it doesn’t. So the average….
        I don’t have time to read those studies, and am not equipped to evaluate their merits or lack of same. News/blabber outlets know this and promote whatever studies show their desired conclusion.

  22. Marko says:

    I’d like to see sterilizing immunity from the COVID-19 vaccine as much as the next guy , but anybody who thinks that’s the only criteria for success isn’t thinking straight , IMO. Everyone involved will be tickled pink if we get a vaccine that relegates COVID-19 to the category of “just another common cold coronavirus”. Sterilizing immunity would be the home run , turning COVID-19 into the sniffles would be a triple , and we’d be happy with it. What we all want to avoid is striking out.

    And the impact on trial data accrual to determine this impact would be minimal , looking at the big picture. From PCR+ to hospitalization is only an extra week or so , to death maybe 3-4 wks. We’ll know the answer just about as fast whether we get sterilizing immunity or just elimination of severe disease.

    Flu “effectiveness” is measured on an ongoing basis by presentation at clinics and hospitals , i.e. , it’s a measure of how well the vaccine reduces the seriousness of the disease. We don’t go into the community and measure how many people didn’t get the flu or had mild symptoms , and whether or not they were vaccinated.

    Of course , those who choose not to be vaccinated , or can’t be for some reason , will be out of luck. COVID-19 will then become more like the flu for the population as a whole , rather than like the common cold. Some will get sick and die , just like for the flu. Life will return to normal, just like for the flu.

    1. Irene says:

      People in the US are way too complacent about the flu. I think we could prevent a lot more deaths from influenza than we do.

      1. Marko says:

        Agreed.

        Even if COVID-19 magically disappeared , as Trump keeps promising it will , we may see a “new normal” in the US where at-risk populations are more likely to socially distance or wear a mask during flu season. Flu vaccine uptake may increase a bit as well. I think a lot of people have been beneficially educated in this regard as a result of the COVID-19 outbreak.

        My point is only that if COVID-19 is reduced to a similar threat level as the flu as a result of a vaccine , the bars will reopen , sports will be played , and life will be essentially as it was before the outbreak. Research will , and should , continue on ways to improve vaccines for COVID , flu , and other infectious diseases. COVID will be one of many diseases we talk about , rather than the only one.

    2. dwh says:

      @ Marko

      I think everyone can agree that sterilizing immunity is the ideal, and likewise, that sterilizing immunity is not the only pathway to a licensed vaccine. However, the question becomes, in a hyper-accelerated development environment for a disease that we don’t completely understand, what are the strategic considerations driving the vaccine development plans of the various stakeholders?

      A critical aspect of that is how do you prove efficacy in a Phase III clinical study. As I indicated in my comments above, vaccine efficacy studies are typically oriented towards reduction in infection frequency not infection severity.

      A few responses to your points:

      “And the impact on trial data accrual to determine this impact would be minimal , looking at the big picture. From PCR+ to hospitalization is only an extra week or so , to death maybe 3-4 wks. We’ll know the answer just about as fast whether we get sterilizing immunity or just elimination of severe disease.”

      The issues with using disease severity as a primary efficacy endpoint in prophylactic mass immunization study are not the timing or technical procedures involved, but instead they have to do with study sample size, subject randomization, and objective evaluation criteria that can be translated into a primary clinical efficacy endpoint. In the case of prevention of infection, symptomatic infection or not is a discrete variable that we have objective assays to measure. In contrast, disease severity is a continuous variable with much more subjective evaluation criteria. In the former case, you can simply test for presence of the virus using a validated assay. In the latter case, the FDA will want you to validate your tools for measuring disease severity in order to accept them as a basis for approval. Your clinical endpoints and measurement tools also makes a big difference in how you power your study. In the case of SARS-CoV-2, disease severity ranges from asymptomatic to mortality, and while we understand a number of the risk factors associated with more severe disease, there are still a lot of unknowns. Based on epidemiological data, it appears that everyone is potentially susceptible to infection, but that severe disease will manifest only in a subset of the population. Unfortunately, viral load / shedding does not appear to be a correlate for disease severity, so you can’t use that as a study endpoint.

      Given these unknowns how do you randomize your vaccine and control groups so that you minimize the risk of introducing bias into the samples? Age? Obviously. Underlying conditions? Yes, but which ones?, Race?, Income?, Body Mass Index? Then you need to factor in that elderly people and those with co-morbidities are the most likely to be hyporesponsive to immunization. What if your vaccine works great to reduce severity in the populations that rarely exhibit severe disease, but not as well in the populations that experience severe disease more frequently?

      The bottom line is that designing and executing an adequately powered appropriately randomized Phase III study for demonstrating an effect on disease incidence is a much more straightforward exercise than trying to prove vaccine efficacy based on reduction in disease severity, especially given what we know of SARS-CoV-2.

      “Flu “effectiveness” is measured on an ongoing basis by presentation at clinics and hospitals , i.e. , it’s a measure of how well the vaccine reduces the seriousness of the disease. We don’t go into the community and measure how many people didn’t get the flu or had mild symptoms , and whether or not they were vaccinated.”

      This is true for population based monitoring but not for clinical efficacy studies of novel vaccine approaches. In a typical Phase III influenza vaccine efficacy study, subjects will be asked to carefully monitor their symptoms and are then contacted ~2-3 times per week to report symptoms that they are experiencing. They often are asked to keep a log of their temperature and other symptoms on a day to day basis. If they exhibit any of the pre-defined symptoms for the study, the protocol specifies that they come in for a culture / PCR test to determine whether they have the disease or not. For influenza, it would typically be temperature >99 F , respiratory symptoms, chills, fatigue, headache, myalgia, etc. The occurrence of even mild symptoms triggers a diagnosis visit.

      As we look at trying to execute rapid Phase III studies for SARS-CoV-2, all of these considerations are having to be addressed under unprecedented timelines with huge gaps in our understanding of the disease. When looked in that context, it is understandable as to why many of the developers development decisions are orienting towards maximizing neutralizing antibody responses and preparing for a traditional disease prevention study design where they are trying to identify a vaccine and immunization regimen that minimizes the risk of symptomatic infection.

      While obviously there is room for a range of strategies and it is great that they are being pursued, the complexity of the pivotal efficacy studies and approval pathway for a vaccine designed to mitigate disease severity should not to be underestimated.

      1. Marko says:

        Look , this is the FDA guidance:

        “The guidance also discusses the importance of ensuring that the sizes of clinical trials are large enough to demonstrate the safety and effectiveness of a vaccine. It conveys that the FDA would expect that a COVID-19 vaccine would prevent disease OR ( my emphasis ) decrease its severity in at least 50% of people who are vaccinated.”

        https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-action-help-facilitate-timely-development-safe-effective-covid

        If vaccine manufacturers have sized and designed their trials to detect only one of the two endpoints , that’s on them. It would be pretty dumb , it seems to me.

        Also , we don’t P3 the annual flu shots before we roll them out. It’s a cassette vaccine and the assumption is that it will be safe and effective. Often , it’s not very effective at all.

        1. dwh says:

          @Marko
          As I indicated, there is a pathway to approval through reduction in disease severity. What I have tried to do is communicate the complications of doing so in the context of developing a vaccine candidate for mass vaccination and why I am skeptical of vaccine candidates that do not appear to offer the potential of preventing infection. The criteria that the FDA has laid out for what constitutes severe disease manifests in roughly 4-6% of infections when looking at a population level. Assuming your assays for severe disease are as clean as that for infection (they aren’t), that would mean, at a minimum, that you would need a study sample population ~20x larger to prove a 50% reduction in disease severity vs. a 50% reduction in infection incidence using the same power and significance criteria. A 20x larger study obviously costs more and takes longer not to mention all of the complicating factors I outlined above. While I do expect the majority of studies to include reduction in disease severity as a secondary endpoint, I am not sure that they will fully power those in their broad population studies. I think the emphasis will be on designing in interim efficacy checks of disease frequency that could enable early approval. It is likely that separate studies in specific high risk populations would then be conducted, perhaps with higher immunization doses to overcome hyporesponsiveness (akin to the Shingles vaccine) and a focus on reducing disease severity in those populations.

          Regarding influenza vaccines, you are correct that seasonal variants of already approved influenza vaccine platforms do not require Phase III studies, but my comments were in reference to the efficacy studies that are performed when any new class of influenza vaccine is developed and submitted for licensure.

          1. Marko says:

            “While I do expect the majority of studies to include reduction in disease severity as a secondary endpoint, I am not sure that they will fully power those in their broad population studies. I think the emphasis will be on designing in interim efficacy checks of disease frequency that could enable early approval.”

            You may be right , but the end result if all vaccine manufacturers adopt this strategy could be that they’re all left holding the bag. An empty “sterilizing immunity” bag , all for the failure to conduct sufficiently powered trials to get to the endpoint that , at the end of the day , may be the only one that’s actually achievable.

            This scenario wouldn’t surprise me , given the way we’ve botched our pandemic response from day one. I also wouldn’t be surprised by a last-minute workaround , where vaccine candidates are approved based on surrogate markers , like neutralizing titers , and we leave it up to the real world to sort out those troublesome “efficacy” issues.

  23. David G Whiteis says:

    Marko — I’m not sure if “life will return to normal, just like for the flu,” even if the scenario you describe comes to pass. Here in Chicago, the director of the city’s Dept. of Public Health has prettuy much dictated that masks, “social distancing” mandates, restrictions on gatherings, and other measures will continue for as long as a vaccine is not “100% effective.” I read ths to mean that until the rate of new cases is 0 (regardless of the seriousness of symptoms), our daily life won’t improve much from what it is now.

    My own personal best-case sceneario would be a vaccine that’s reasonably effective — let’s say around 70% or so — along with a therapeutic (LAM-002A looks promising) that could be administered to people in the early stages of infection, which could diminish their symptoms to a flu-like level. Thus, most people would be protected, and most of those who weren’t wouldn’t get very sick.

    I’m afraid, though, that this will not be enough to satisfy our “Zero New Cases or Bust!” purists, who’ll insist on imposing pandemic-like social conditions on us until the day when we’ve achieved perfection — i.e., total elimination of the virus entirely (ala smallpox). In other words, we’re going to be masking, “social distancing,” isolating ourselves from one another, and “hugging” our friends via Zoom (or whatever comes along to replace it) for the rest of our lives. And our children will have to learn to go through life without ever sharing a hug with a friend, or a smile with a stranger.

    1. Irene says:

      But that presumes we’re NEVER going to get test/trace/quarantine going. Near-universal testing is how we get beyond the need to isolate people who aren’t infected, because then we will know (not perfectly, but enormously better than we do now) who is infected.

      1. David G. Whiteis says:

        I hope we can do that. Realistically speaking, even if we had good leadership and a truly working and effective public health system, it would be a daunting task. Most countries where testing/tracing has been effective are either significantly smaller (both geographically and in terms of population) than the U.S., or they have authoritarian governments capable of imposing restrictions on personal privacy (e.g., South Korea, which used data from security cameras and credit card transactions to follow people’s movements) which Americans, understandably, would never tolerate.

    2. confused says:

      But people just won’t do those things indefinitely, whatever authorities *say* they should do.

      1. David G Whiteis says:

        Right — and if they don’t, the infection rates will creep up again, and sooner or later we’re back where we started (or close enough that we never get off the merry-go-round to hell).

        See the paradox? The “solution” to the problem — [anti-]social distancing, covering our faces with masks, avoiding public gatherings — is the exact inverse of what we need most desperately in times of crisis: close human contact. The worse things get, the more we’re compelled to do the very opposite of what’s necessary to help us survive them with our minds and souls intact. The very things that reflect the “better angel of our nature” — hugging one another, raising our voices together in praise, gathering in fellowship — have become cast as vectors of death and pestilence. (My own heart broke recently when I revisited a YouTube clip of the gospel singer Mavis Staples singing “Touch A Hand, Make A Friend” — to think that such a simple yet profoundly wise and healing affirmation of faith and optimism has suddenly been taken from us, only to be replaced by “Get Away! Don’t Touch Me!” — and that we may never get it back.)

        That disconnect between two necessities — what it takes to stay alive, and what it takes to sustain a life worth living — is a tragic paradox for which there may be no resolution. It’s tantamount to telling a sick person: “You’ll need to take this drug to stay alive, but the side effects will be so severe that you’ll probably wish you weren’t.”

        1. confused says:

          Nah, I don’t think it’ll be nearly that bad. A vaccine wouldn’t have to be all *that* high effectiveness to drop the levels of illness/death low enough that we could just live with it like we do any of the other circulating respiratory viruses, even in the absence of any masks or social distancing measures.

          And treatments will get better too. That will have a multiplicative effect with the vaccine.

          And what’s the earliest plausible timeline for getting a vaccine out there? Even if we get the phase III data in October and it looks good and the FDA approves it basically instantly… distribution will take time.

          By December the US will probably be >20% infected, at least in the more populated areas, which will probably slow the spread down somewhat. And by then people will just be tired of all this and will take the vaccine as a definitive ending to it.

          I would be *extremely* astonished if people aren’t back to full capacity in restaurants and bars, with no masks in sight, a year from now. (Or even by Easter 2021.)

          1. David G Whiteis says:

            ” . . . people will just be tired of all this and will take the vaccine as a definitive ending to it.”

            THAT part I agree with. In fact, because distribution/administration of the vaccine will probably happen in stage — medical care workers/first responders/”essential” workers first; high-risk populations next; then expanding out into the general population — people will have time to observe and see whether it’s really safe and effective. By the time it gets more widely distributed (probably mid-2021 at the earliest), general confidence in it might have improved. There will still, though, have to be a major initiative to convince African-American people that it’s safe — for very real and legitimate reasons, there’s a lot of distrust in that community.

        2. rtah100 says:

          As a British person, the chance of my touching a family member is low and a stranger is non-existent. I don’t see what all the fuss is about.

          And I am not really joking. I could do without Mavis Staples emoting at me or happy clappy singing. I’m more worried about never going to the theatre or a restaurant again but these at least admit of engineering solutions (high-flow ventilation and UV light disinfection).

  24. David G Whiteis says:

    . . . also, by the way — I admire Dr. Fauci for being honest enough to point out that a COVID vaccine, especially a first-generation one, will most likely not be “fullly” effective. I fear, though, that this will make even more people reluctant to be vaccinated. People tend to think in terms of absolutes — the reaction is likely to be, “Why should I? It’s not going to work, anyway.” If this is the case, the struggle ahead of us will be even more dire and thankless than we’re fearing.

  25. loupgarous says:

    Cancer patienta with impaired immune systems accept the limitations that most of us are now dealing with during the pandemic. Instead of cancer, we’ll all have a reservoir of a virus that will mutate from time to time to affect us all more than we’d like. That’s non-negotiable. It won’t listen to our pleas, our cries of anger or our protests. No matter how it came here, it’ll be with us.

    Best case, we’ll learn how to deal with it. We’ll learn that masks aren’t submission to over-reaching government, but tools we must use to protect each other, and that social distancing is how to show each other love, affection and consideration. We’ll do that because we can be fighters who won’t give up on each other or ourselves.

    Worst case… is worse. It can be worse in many ways. Using the pandemic to beat each other up won’t help. It’s just a way of letting the disease win. So is indulging in despair over our situation. Things won’t go back to “normal”. It’s not just. It’s not fair. Deal with it.

    This is the new “normal”. We need to accept the good things, hope for new vaccines and treatments and hope that they take us closer to where we were when this pandemic started. We can learn that we can beat even the worst things that happen to us. Worse things will happen to us than this.

    Each of us is in charge of dealing with that. And that’s how we get payback against the pandemic.

    1. confused says:

      >>Things won’t go back to “normal”.

      Why do you think not? I really can’t see them *not* going back to normal as soon as there’s a vaccine and/or a really effective treatment. People are really fed up with this.

      But then, I live in a state (TX) where people are generally not taking it as seriously as elsewhere. I think people here will probably be mostly back to normal before we even *get* a vaccine, honestly, probably within a few months as the South/West peak wanes.

      1. eub says:

        Normal behavior in the presence of circulating virus results in abnormal circumstances which result in altered behavior. In the short term, when infection rate reaches the point of overwhelming the healthcare system, we’ve seen that people respond, even if they hadn’t before. (There is no effective treatment if you can’t get it.) Guess we can hang out right around healthcare saturation if we choose, though it’s sure a rough place to choose to sit. In the longer term, I expect that once people know somebody who died, or somebody whose relative died, it may affect how they think about being a transmission route for the virus. Could be wrong.

        The virus doesn’t care how much work we’ve put in or how we feel. It’s got no memory besides current level of circulation and current level of immunity.

        1. confused says:

          >>Normal behavior in the presence of circulating virus results in abnormal circumstances which result in altered behavior.

          Not just the existence of circulating virus, it requires a certain fairly high danger level. Flu doesn’t really affect our behavior, lots of people in the US don’t even bother to get flu shots.

          So, once a vaccine drops COVID’s danger level to flu-level or below, and once it’s no longer .
          “new and unknown”, I don’t think it will affect behavior much.

          And the vaccine won’t have to be terribly high-effectiveness to achieve that, since there will probably also be better treatments and slower spread because a large chunk of the US population already has had it before the vaccine even came out.

          I really wouldn’t expect to see more spikes that risk hospital capacity, except maybe in places that haven’t been hit hard yet.

          1. eub says:

            Some hypothetical effective vaccine, sure. That was in response to your
            “I think people here will probably be mostly back to normal before we even *get* a vaccine, honestly”

          2. confused says:

            I was more talking about some parts of the US hitting enough immunity to reduce transmission rates a lot (though likely not full-on “herd immunity”) before a vaccine is widely available, combined with an, IMO, likely lack of will to take further measures even if infection/death rates do go up.

            covid19-projections.com has a model that suggests that TX (my state) is already at 20% of population infected. That might be high, but it’s got to be double-digit at this point. Even if a vaccine is *approved* in Oct or Nov, it will take more time for everybody to get vaccinated. So I could totally see TX and other nearby states ending up with very high immunity-via-infection levels.

          3. David G Whiteis says:

            “. . .I could totally see TX and other nearby states ending up with very high immunity-via-infection levels.”

            But again, remember — the morbidities associated with COVID are still being learned about, and the more we learn, the more grim they appear. A lot of suffering for a lot years will be the price of those “immunity-via-infection levels.”

          4. David G Whiteis says:

            . . . and actually, if I know my publc-health policy types (and I think I do, having worked and associated with many of them for a lot of years), they won’t be satisfied with “hitting enough immunity to reduce transmission rates a lot” or even a drastic reduction in “spikes that risk hospital capacity.” I already mentioned that the director of Chicago’s Department of Public Health is holding out for a “100% effective” vaccine before she’ll consider relaxing “distancing” and masking requirements, allowing large outdoor gatherings to occur again, re-open bars and nightclubs to full capacity, etc.

            Here’s the quote: ““I don’t know we’ll ever get to a point where COVID will be eradicated, to be perfectly honest. Life will continue to look different. A vaccine will probably start to be available in early 2021, but it will likely take a full year to a do a full rollout of that, and the vaccine will probably not be 100 percent effective.”

    2. eub says:

      Wee bit dusty in here.

      I had a family medical situation where for some months, about a year, every respiratory virus was a crapshoot that a family member would be intubated for weeks again, and all the possible worse sequelae of the ICU. We didn’t go out much. And some friends were astonished by how we were living — you can’t just stop living! It was a big change, and a negative one, but from inside /I’ve met “stop living” and this is not it./ Boy, if we could have gotten through by wearing masks instead, I’lll tell you that would have been heavenly.

      Some people now are in that direct a choice, where someone they know is at risk. Most people are altruistic when it’s their own grandma. Altruism is less automatic when the person at risk is two hops away, much less the abstract idea that if we pull together we can get R < 1. I hope we can learn it.

    3. David G Whiteis says:

      ” . . .social distancing is how to show each other love, affection and consideration.”

      Uh-huh — “I LOVE YOU! GET AWAY FROM ME! DON’T TOUCH ME!”

      If this is our futture, I don’t want to be in it.

    4. David G Whiteis says:

      ” . . .social distancing is how to show each other love, affection and consideration.”

      Uh-huh. “I LOVE YOU! GET AWAY FROM ME! DON’T TOUCH ME!”

      If this is our future, I don’t want to be in it.

      1. David G Whiteis says:

        I apologize for the double post. I’m not flaming or trolling. It didn t get posted, so I thought something went wrong with the sysem.

        Again, my apologies — although I do stand by what I said.

  26. David G Whiteis says:

    “. . . masks aren’t submission to over-reaching government, but tools we must use to protect each other, and . . .s ocial distancing is how to show each other love, affection and consideration. We’ll do that because we can be fighters who won’t give up on each other or ourselves.”

    But the fact still remains that people can stay “distanced” from each other, not hug or touch each other, and not be able to see each other’s faces, for just so long. What we’re doing now (out of necessity) is incredibly isolating, and it will have serious emotional and mental health effects — in fact, from what I’ve been reading, it already has. We’re seeing an increase in depression and stress-related physical and mental conditions, and we’ve only been “distancing” for a little over three months. Human beings are social animals; it’s part of our makeup. And yes, touch and physical contact are part of that, too. We desperately need to find a way to get back to relating to one another like “real” human beings again.

    A society of “people without faces” who are afraid to get within six feet of one another is a stressed (and lonely) society. It’s not like condoms or seat belts — those are physical barriers or restraints that cen be adjusted to. This goes deeper, into the very soul and essence of what it means to be human. Without the glow of empathy that comes from “face-to-face” encounters and communication (there’s a reason we use that term!), the glow of our humanity is extinguished, as well.

    We may well be caught between the twin poles of a tragic paradox, neither of which bodes well for our survival (physically/emotionally/spiritually): To stay alive, we must forge a life for ourselves that is not worth living.

  27. David G Whiteis says:

    New topic of discussion?

    In theory I support the idea of compulsory vaccinations; however, I believe this would be politically infeasible in the U.S. (perhaps not in some other countries, such as many Asian countries, where people are more used to following orders for the “common good”). Here, though, if it became evident that there was a chance that vaccinations might be made compulsory (and/or that some kind of federal “registry” would be involved), even more Americans would probably jump on the ant-vox bandwagon, inflaming the controversy and the resistance even further. We would also have to make sure that before such laws were enforced, a vaccine would be accessible and available to all Americans, including low-income people, people of color,and people living in remote areas. Poverty, race, or geographic location should not be factors in determining whether people have access to necessary goods and services.

    Nonetheless, I think that employers can, and should, require proof of vaccination among their employees. I might also suggest that in the absence of a governmental mandate, at least some private entities — restaurants, bars, performance/entertainment venues such as nightclubs, show lounges, auditoriums, gambling casinos, etc. — could have an impact by mandating that proof of vaccination would be required for entry (not unlike having show an ID to purchase alcohol). It might mean fewer patrons for a while, but it couldn’t be much fewer than the current “25% – 50% capacity” restrictions that a lot of places are being held to right now — and, in the long run, it would attract more patrons who otherwise might not feel safe going to these places. It would also, one hopes, encourage vaccine “fence-sitters” to get vaccinated, just so they can join the fun.

    In other words, a “carrot” approach rather than a “stick” approach might be the most feasible,and the most likely to produce good results. It’s possible, also, that this could lead to a kind of positive, proactive social “shaming” of people who refused vaccination (I could actually envision “Vax Parties” springing up around the country, making it “cool” to be vaccinated.) If public figures like entertainers and sports celebrities added their voices to the initiative, this could help things even more. The faith community needs to step up; so do influential and respected public figures from all walks of life. Given the especially strong resistance among people of color in the U.S., I can envision Barrack and Michelle Obama getting vaccinated in front of the cameras, and Whoopi Goldberg and her colleagues doing the same thing on The View. The hip-hop community should launch a full-scale advocacy campaign (especially now that Kanye West seems to be delivering anti-vax messages); other prominent figures from popular culture, including athletes, also need to do their part.

    Creative thinking will be essential in helping bring about a situation in which we can return to a post-COVID “normal.”

    Any thoughts???

  28. Sue D says:

    Good ideas, requirement for college and school entry could be added.

    1. David G Whiteis says:

      I agree — but again, only if the vaccine is available, accessible, and affordable in all communities. No child should be prohibited from going to school because he or she lives in the
      “wrong” neighborhood. (Question: Could we kill two birds with one stone by setting up temporary vaccination sites in school facilities, and allowing college health clinics to administer vaccinations? If I recall correctly, either the measles or polio booster shots were administered in school when I was in elementary school, so I think this has been done before.

  29. Marko says:

    New therapeutic coming soon ? :

    Relief Therapeutics Sees 60-70% Chance of COVID-19 Drug Approval

    https://www.nytimes.com/reuters/2020/08/08/business/08reuters-health-coronavirus-relief-hldg.html

    1. David G Whiteis says:

      Interesting — Just for the sake of clarity, this would be administered to people with the most serious symptoms, right? The Phase III trials will be conducted on patients who are severely ill.” That excellent news in terms of lowering the death rates and reducing hospital stays. What we still need to develop, though, is the kind of therapeutic that’s been mentioned here, which could be administered to people who have just begun to present symptoms, to reduce their seriousness to something approximating a flu-like level. (In other words, Marko, as you suggested — “My point is only that if COVID-19 is reduced to a similar threat level as the flu as a result of a vaccine . . . life will be essentially as it was before the outbreak. Research will , and should , continue on ways to improve vaccines for COVID , flu , and other infectious diseases. COVID will be one of many diseases we talk about , rather than the only one.”)

      Unless I’m misreading this, RLF-100 is not that kind of a palliative. Am I getting this wrong?

      1. Marko says:

        “Unless I’m misreading this, RLF-100 is not that kind of a palliative. Am I getting this wrong?”

        I have no idea.

        I’ve read that the drug is also effective for erectile dysfunction , so male COVID patients may become more frisky during their hospital stay. That might be considered an adverse side effect by the nursing staff. At the very least it would require additional caution when proning such patients.

  30. New PI says:

    I mentored a student that thought he had a unconventional idea about how to treat an infection. He was clearly pro-trump. I cant wait to fire his ass tomorrow. Lol.

  31. Ellen says:

    it’s not being tested in children so it should not be used to vaccinate them.even if they lower the dose it means nothing.also what if any are the long term effects from this vaccine? I dont care how gòod a company is trying to get a vaccine out there it should not be allowed.ebola was worse than covid 19 could ever be and it took 5 years.i cant think of anything more reckless than rushing this vaccine no matter what the experts say.experts have been known to be wrong.i could right a book of examples.never the less each adult 18 and over must make his or her own choice regarding the rushed vaccine.parents especially should be given the option if at all meaning we just dont know how it will effect children now and later on

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