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Possible vaccines/treatment(s) for Coronavirus

Valneva has expanded its VLA2001 UK trials: the COV-Compare phase 3 study has added adolescents (12-17 years) and its earlier UK phase 1/2 study will now investigate six-month post-second-dose boosters for earlier participants. A trial focusing on VLA2001 in elderly volunteers is also underway in New Zealand.
 
Saw this under politiFact


A headline on Zero Hedge, which we’ve fact-checked before, alluded to ivermectin by stating:

"Pfizer Launches Final Study For COVID Drug That's Suspiciously Similar To 'Horse Paste.’"

The post was flagged as part of Facebook’s efforts to combat false news and misinformation on its News Feed. (Read more about our partnership with Facebook.)


"So no reason to call the Pfizer drug ‘Pfizermectin,’" Garry said. "Clever, but no basis in fact."

I had to look up protease.

"The Pfizer compound, by contrast, was designed explicitly to target the protease of the virus," he said. "Ivermectin is an anti-parasitic drug that has a distinct mechanism of action against parasites and may happen to have some similarities, by chance, with the Pfizer compound."
 
Saw this under politiFact







I had to look up protease.

Looks like fake news to me. Happy to be corrected but…

I worked on an ivermectin project about 25 years ago! Fun fact, one batch a year is made and sent to Africa to treat African River Blindness for free :thumbs:
 
Regarding vaccines tuned to specific variants, here an investigation from Durban/UCL/UWash/others, where they mapped neutralisation of evolved virus (here D190, found in some HIV patient cases) and ancestral D614G, beta/B.1.351 and delta/B.1.617.2 variant viruses by antibodies elicited by each of those VOC in SARS-CoV-2 convalescent individuals.

Beta virus exhibited a moderate 7-fold escape and delta only a 2-fold escape from neutralisation by ancestral (D614G) variant elicited sera. However delta demonstrated a 12-fold escape from beta elicited immunity, whilst beta virus exhibited 34-fold escape from delta immunity. Evolved virus had 9-fold escape from ancestral immunity, 27-fold escape from delta immunity, but was effectively neutralised (3-fold escape) by beta immunity.
Summary map of serological distances between beta, delta, D614G ancestral and immunocompromised-evolved D190 SARS-CoV-2 variants.

The researchers concluded that beta and delta are serologically distant, further apart from each other than each is from their common ancestor. A key observation was that virus (D190) evolved in episodes of prolonged infection (eg the immunocompromised) is serologically closer to beta and further from delta. These results suggest that SARS-CoV-2 is diverging into distinct serological phenotypes and that vaccines tailored to one variant may leave populations vulnerable to infections with another.

Thus it may be best to avoid dedicated, specific VOC-tuned vaccines and either stick with the backbone of a common ancestor (eg D614G) or develop multivalent vaccines (such as delta/beta/D614G). Widespread deployment of a vaccine that is specifically targeting delta/B.1.617.2 might create a future opening for beta/B.1.351 and progeny.
DOI: 10.1101/2021.09.14.21263564.
 
A couple of preprints of relevance to vacinee PCR/antigen testing, viral loads, infection and possible implications for transmission.

From Oxford (and others) a retrospective observational cohort study of contacts of SARS-CoV-2-infected index cases using contact testing data from England, investigating variation in transmission between alpha/B.1.1.7 and delta/B.1.617.2 since second dose vaccination.

Through large-scale contact tracing data, they show that BNT162b2 and AZD1222 vaccination both reduce onward transmission of SARS-CoV-2 from vaccinated individuals (BNT162b2 moreso than AZD1222). However reductions in transmission are lower for both vaccines for delta compared to alpha. Both vaccines protect against delta but to a lesser degree than alpha, particularly in milder cases (where delta infection rates are higher and transmission more likely) and this protection wanes over time (faster for BNT162b2 than AZD1222).
Estimated probability of a positive PCR test in contacts by time since second vaccination in index cases (A) and in contacts (B), variant, and vaccine type.
They found that most of the effect of vaccines persisted after adjusting for Ct values, implying that factors other than PCR-measured viral load at diagnosis are important in vaccine-associated transmission reductions:
It is possible vaccination acts by facilitating faster clearance of viable infectious virions, but leaving damaged ineffective virions behind that still contain PCR-detectable RNA. This may mean antigen assays have advantages in predicting the risk of onward transmission in those vaccinated, but this needs further study.
DOI: 10.1101/2021.09.28.21264260.

Separately, a study (UCDavies/UCSF/Berkeley) found no significant difference in PCR cycle threshold values between vaccinated and unvaccinated, asymptomatic and symptomatic groups infected with delta/B.1.617.2, regardless of age or gender.
SARS-CoV-2 cycle threshold values in asymptomatic, symptomatic, vaccinated, and unvaccinated individuals in California.

In this analysis, over 20% of positive, vaccinated individuals had low PCR Ct-values (<20), a third of which were asymptomatic when tested. If such cases carry a high viral load they be a major factor in driving the on-going pandemic.
The data gathered in this study during the surge of the Delta variant strongly support the notion that neither vaccine status nor the presence or absence of symptoms should influence the recommendation and implementation of good public health practices, including mask wearing, testing, social distancing, and other measures designed to mitigate the spread of SARS-CoV-2.
DOI: 10.1101/2021.09.28.21264262.
 
From the US (Kaiser) a retrospective cohort study of several million vaccinees (12+ years) assessing BNT162b2 effectiveness against SARS-CoV-2 infection (by variant) and COVID-19 related hospital admission for up to 6 months post second dose.

Effectiveness against SARS-CoV-2 infection was 73% (95%CI:72-74) and against COVID-19-related hospital admissions was 90% (95%CI:89-92). This effectiveness declined from 88% (95%CI:86-89) to 47% (95%CI:43-51) from one month to five months after second dose. Vaccine effectiveness against infection specifically by delta/B.1.617.2 declined from 93% (95%CI:85-97) to 53% (95%CI:39-65) from one month to five months after second dose. For other (non-delta) variants this waned from 97% (95%CI:95-99) to 67% (95%CI:45-80) from one month to 4-5 months after second dose. However vaccine effectiveness against hospital admissions for delta infections, across all ages, was 93% (95%CI:84-96) for up to 6 months post second dose.
Adjusted estimated vaccine effectiveness against SARS-CoV-2 infection by variant.
Importantly, they add:
Our variant-specific analysis suggests that reductions in BNT162b2 effectiveness over time are likely to be primarily due to waning vaccine effectiveness rather than the delta variant escaping vaccine protection given that effectiveness against delta variant infections was more than 90% within 1 month of full vaccination, reductions in effectiveness in infections by time since being fully vaccinated were observed irrespective of SARS-CoV-2 variant, and effectiveness against hospital admissions due to the delta variant was very high over the entire study period.
DOI: 10.1016/S0140-6736(21)02183-8.
 
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On the potential effect of vaccination on long covid symptoms and recovery, a matched cohort study (INRIA/Paris/Columbia) of several hundred French cases emulating a target trial.

This found that, after 120 days, long covid was significantly less severe, with less impact on patient's lives, in the vaccinated group compared to the control. It was found that vaccination (here that cohort may have received any one of four approved vaccines - BNT162b2, mRNA-1273, AZD1222, Ad26.COV2) doubled the remission rate of long covid symptoms.
Cumulative event curve for complete remission of long COVID symptoms among vaccinated patients and controls.

Explanatory thread.
 
From Qatar, a study of mRNA vaccine effectiveness (in almost 1 million persons receiving two does, standard interval, of either BNT162b2 or mRNA-1273), that supports the ideas that waning of immunity is largely independent of age and variant type. Additionally that over the six months studied, whilst efficacy to infection may decline (around months 3-4 post second dose), efficacy to hospitalisation and death was maintained at a high level (96% or higher). Furthermore, efficacy was seen to wane to a greater degree than in countries where a much longer first-second dosing interval was instituted.
DOI: 10.1056/NEJMoa2114114.
 
From Rockefeller, a study investigating longitudinal B cell response in non-convalescent vaccinees and comparing it to that of vaccine response in recovering patients.

Convalescents produce memory B cells which express increasingly broad and potent antibodies that are resistant to mutations, elevated further by (mRNA) vaccination, producing high levels of plasma neutralising activity against all variants tested (alpha, beta, iota, gamma, delta). In SARS-CoV-2 naive individuals a different outcome was observed:
Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge 5 months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response.
The authors suggest that boosting vaccinated individuals with currently available mRNA vaccines will increase plasma neutralising activity but may not produce antibodies with equivalent breadth to those obtained by vaccinating convalescent individuals. Key perhaps, however, is that they observed that the memory B cell compartment continues to evolve for up to 5 months after mRNA vaccination. This suggests ideally one would seek such an interval between exposures to antigen, particularly in the case of boosters, in order to maximise memory based immunity.
DOI: 10.1038/s41586-021-04060-7.
 
Molnupiravir sounds very useful as long as people take it early enough.

Indeed - perhaps looks less promising in patients - trials in India being halted for moderate-severe cases.
Aurobindo Pharma Ltd wants to discontinue a late-stage trial of molnupiravir in moderate COVID-19 patients, the regulator's expert committee said on Friday.

"There is no significant efficacy against moderate COVID and the effective efficacy is towards mild cases," the source said on condition of anonymity due to the sensitive nature of the discussions.
 
Curevac CVnCoV mRNA vaccine final data from their phase 2b/3 trial (40,000 participants) have been announced. It demonstrated vaccine efficacy of 48% against COVID-19 of any severity across all age groups and 15 variants. For participants aged 18 to 60 and across all 15 variants vaccine efficacy was 53% against disease of any severity, 77% against moderate and severe disease and it provided 100% protection against hospitalisation or death. A favourable safety profile was observed in all age groups. Curevac are now developing a second generation mRNA candidate, CV2CoV, with the aim of clinical trials later this year and regulatory approval in 2022.
Curevac confirm that they are withdrawing their first generation mRNA vaccine (CVnCoV) from regulatory review. They are pursuing development of their second generation mRNA vaccine (CV2CoV), partnering with GSK, built with tweaked non-structural regions around the ORF sequences (akin to the technique used in BNT162b2, mRNA-1273 to initially shield the vaccine from the immune system during delivery).
 
The NIH booster mix and match study results preprint is now available (FDA 2-day committee meeting on boosters and mixing starts tomorrow).

This US phase 1/2 clinical trial investigated safety, reactogenicity and (humoral) immunogenicity in 458 adults who previously received one of three US FDA-approved COVID-19 vaccines at least 12 weeks prior, wherein each received a booster injection with one of mRNA-1273, Ad26.COV2.S, or BNT162b2 30-mcg, making nine combinations in total.

The authors reached similar conclusions to previous work from the UK and Germany on mixing AZD1222 and BNT162b2 (see eg posts #1429 & #1434) - the combinations were well tolerated and safe, with comparable reactogenicity to the original two-dose series. Elevated antibody responses were measured in every instance. In particular mRNA vaccines (both BNT162b2 and mRNA-1273) significantly boosted J&J Ad26.COV2.S (from a lower study baseline).
SARS-CoV-2 IgG binding antibody titres to wildtype (A-C) and pseudovirus neutralisation IU50/mL titres to D614G (D-F) at study day 1 (baseline), study day 15 (post-boost), and study day 29. Convalescents are indicated by red data points. IgG serum binding antibody response to wildtype, alpha and delta VOCs for each booster/original series combination.
In summary, this preliminary report demonstrates that boosting with any of the three vaccines currently licensed or authorized for emergency use in the US will stimulate an anamnestic response in persons who previously received of the primary series of any of these vaccines. Homologous boosts provided a wide range of immunogenicity responses, with heterologous boosts providing comparable or higher titers. Reactogenicity and adverse events were similar across booster groups. These data suggest that if a vaccine is approved or authorized as a booster, an immune response will be generated regardless of the primary Covid-19 vaccination regimen.
DOI: 10.1101/2021.10.10.21264827.

e2a: FDA presentation of this study data (15Oct2021) also covered variants, indicating heterologous boosts appear to produce immunoresponses which would suggest good coverage of VOCs (B.1.1.7/alpha and B.1.617.2/delta).
 
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Pfizer/BioNTech submit data (see post #1492) to the EMA for regulatory approval of a two-dose 10µg regimen of BNT162b2 in children 5-12 years of age.
 
From a letter (NEJM) describing a small (31 BNT162b2; 22 mRNA-1273; 8 Ad26.COV2.S) US longitudinal immunoresponse study, a suggestion that viral vector vaccines might (eventually) promote better CD8 T cell responses than mRNA vaccines (at least in those with no prior infection).

The, by now, familiar elevated initial antibody responses were seen in the mRNA vaccinees, with a noticeably lower response for J&J/Janssen Ad26.COV2.S. However, by month 8 the mRNA antibody responses had declined significantly, whilst Ad26.COV2.S induced CD8 was significantly higher (CD4 somewhat lower; antibody decline less pronounced than for mRNA).
Kinetics of humoral and cellular immune responses elicited by the BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines.
Importantly - the authors state that there were no convalescents in the study sample (nor breakthrough infections), though this is described as being "self-reported" (there is no indication of screening for anti-N). Likewise no participants on immunosuppressants (also self-reported).

Observations could be related to (viral vector v mRNA) half-life of antigen in the body (eg perhaps gut) and/or standard mRNA dosing interval being so short (consider affinity maturation truncation). Alternatively (or also), just to complicate matters further, some of the J&J vaccinees, due to low initial antibody levels relative to mRNA vaccinees, could conceivably have been more prone to asymptomatic/paucisymptomatic infections mid-study, resulting in subsequent further broadening of T cell responses and slightly elevated antibody response (obfuscating decline).
DOI: 10.1056/NEJMc2115596.
 
The phase 3 Cov-Compare trial topline results for Valneva's VLA2001 inactivated, adjuvanted (CpG-1018) vaccine have just been announced (4,012 participants, 18+ years).

It met all co-primary endpoints, provoking a significantly stronger immunogenic response than AstraZeneca ChAdOx1/AZD1222. Geometric mean titres for neutralisation antibodies (live virus assay) were 803.5 (95%CI:748.48-862.59) for VLA2001, compared to 576.6 (95%CI:543.6-611.7) for AZD1222. Seroconversion rates were non-inferior. Broad T cell responses were seen against spike, nucleocapsid and membrane proteins.
SARS-CoV-2 live virus neutralising antibody levels VLA2001 compared to AZD1222 at day 43.
VLA2001 was well tolerated with significantly less adverse reactions compared to AZD1222. There were no severe cases of COVID-19 in either arm of the trial (during a period dominated by delta/B.1.617.2). Extension studies for booster, paediatric and elderly trials are underway. MHRA rolling submission is ongoing with final submission due in November and approval is hoped for by the end of the year. EMA pre-submission discussions have begun.

(Think I know what booster I will be looking for next year).
 
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The phase 3 Cov-Compare trial topline results for Valneva's VLA2001 inactivated, adjuvanted (CpG-1018) vaccine have just been announced (4,012 participants, 18+ years).

It met all co-primary endpoints, provoking a significantly stronger immunogenic response than AstraZeneca ChAdOx1/AZD1222. Geometric mean titres for neutralisation antibodies were 803.5 (95%CI:748.48-862.59) for VLA2001, compared to 576.6 (95%CI:543.6-611.7) for AZD1222. Seroconversion rates were non-inferior. Broad T cell responses were seen against spike, nucleocapsid and membrane proteins.

VLA2001 was well tolerated with significantly less adverse reactions compared to AZD1222.

(Think I know what booster I will be looking for next year).

So much for the tories saying it wouldn’t pass regulatory approval while they were cancelling the UK orders.
 
From Sweden a mix and match study comparing AZD1222, BNT162b2 and mRNA-1273, during which time infections were dominated by delta/B.1.617.2.

Over a follow-up time of up to six months since vaccination, symptomatic COVID-19 infection was confirmed in 187 (2/100k days) heterologous and 306 (7.1/100k days) individuals from the unvaccinated control group. Adjusted vaccine effectiveness was 67% (95%CI:59-73) for AZD1222/ BNT162b2, 79% (95%CI:62-88) for AZD1222/mRNA-1273. Both heterologous regimens had an effectiveness of 68% (95%CI:61-74) compared to 50% (95%CI:41-58) for homologous AZD1222.
DOI: 10.1016/j.lanepe.2021.100249.

New ONS results covering both alpha/B.1.1.7 and delta/B.1.617.2 dominated periods might suggest any (UK) vaccination has delivered 67% (95%CI:64-70) efficacy against any delta infection compared to 79% (95%CI:73-84) for any alpha infection, with 75% (95%CI:71-78) for symptomatic delta and 95% (95%CI:91-98) for symptomatic alpha. BNT162b2 exhibited 73% (95%:70-76) efficacy to any delta infection compared to 62% (95%CI:58-66) for AZD1222. For symptomatic infection BNT162b2 exhibited 83% (95%CI:79-86) to delta whilst AZD1222 was 69% (95%CI:64-74). However care should be exercised as, due to these observations being made over different windows of time (alpha Dec2020-May2021 and delta May-Aug2021) they may be confounded to degrees by both waning of immunogenicity and behavioural/NPI factors.
 
From the UK (PITCH and others) a study of immunogenicity when extending the dosing interval of BNT162b2.

It found that an extended interval (up to 14 weeks ) between doses was highly protective, with higher neutralising antibody levels compared to the standard, shorter regimen. In particular, virus-specific CD4+ T cells are enriched and B and T cell pools maintained. This suggests that the extended interval leads to effective humoral and cellular responses. The (by now) classic responses of hybrid immunity in the previously infected cohort, and their broader responses to variants, were also noted.
Comparison of IgG and T cell responses to original wildtype (Victoria) and VOC four weeks after second dose of vaccine.
In conclusion, the immunogenicity of longer regimens appears robust, and indeed for antibody measurements, improved over the conventional 3-4 week regimen. We provide evidence that T cells are induced and sustained during the longer period between doses in the 6-14 week regimen, but there is an impact of dosing interval on the relative proportion of T cell subsets. Ongoing studies in this cohort will monitor the durability of antibody and T cell responses 6 months after a 2nd vaccine dose delivered in an extended dosing interval, and response to 3rd “booster” doses where given. For policy makers, optimal dosing intervals may depend on community prevalence, population immunity from natural infection, circulating variants of concern and vaccine supply. A short dosing interval gives early protection, whereas an increased interval appears to improve peak neutralizing antibody levels.
DOI: https://doi.org/10.1016/j.cell.2021.10.011.
 
From Sweden (Karolinska and others) a longitudinal study of post-vaccination immune response, following AZD1222 vaccinees for three months and BNT162b2 vaccinees for seven months (in total a few hundred healthcare workers, predominately female, aged around 40-60 years).

Vaccinated convalescents were found to have both higher neutralising titres and less rapid decline of such in both AZD1222 and BNT162b2 cohorts compared to previously uninfected vaccinees. Notably, titres held up to (what appear to be) efficacious protective levels for up to 3 months for AZD1222 recipients and for up to 7 months for BNT162b2 recipients.
Binding and pseudo-neutralising antibody titres over time following BNT162b2 and AZD1222/ChAdOx1 vaccination with and without prior SARS-CoV-2 infection.
Neutralizing capacity against ten SARS-CoV-2 variants analysed, including all four VOCs, remained substantially higher in SARS-CoV-2 recovered vaccinees as compared to SARS-CoV-2 naive vaccinees throughout the study period. Although vaccinated SARS-CoV-2 recovered individuals may eventually need a booster, these findings suggest that vaccine in immune competent SARS-CoV-2 recovered evokes antibody levels that are sufficient for protection during a longer time period than those rendered in SARS-CoV-2 naïve vaccinees.
DOI: 10.1101/2021.10.16.21264948.
 
So much for the tories saying it wouldn’t pass regulatory approval while they were cancelling the UK orders.
Valneva CFO yesterday (R4 interview) said they were shocked by the cancellation, particularly as no immunogenicity trial data was available at the time, and that there was no clarity in communications from government ministers.
 
From the US (Vyriad/Imanis) an oral active vaccine booster candidate, VSV-SARS2(+G). This is built around a replication competent vesicular stomatitis virus (VSV) whose glycoprotein code, which provides the structure that mediates entry into mammalian cells, is effectively replaced with the sequence for (early type) SARS-CoV-2 spike protein (C terminal domain slightly modified), plus some tweaks to tune replication (plasmids encoding the original glycoproteins are added back prior to harvesting).
Generation and characterisation of VSV-SARS2(+G) virus.
In animal models an oral dose for previously (IM) vaccinated subjects was demonstrated to significantly boost buccal and bronchial neutralising antibody titres.
 (B) IgG titres against spike; (C) neutralising antibody titres using the live SARS-CoV-2 spike VSV pseudovirus and (D) a lentiviral pseudovector displaying the spike protein.
Clinical testing of oral VSV-SARS2(+G) vaccine is now planned.
DOI: 10.1101/2021.10.16.464660.
 
A study (Northwestern) investigating modulation of the prime dose of SARS-CoV-2 vaccine: less indeed appears to be more.

In animal models they observed that a fractional first dose (1000-fold lower) of a viral vector (AD5 based) SARS-CoV-2 vaccine resulted in greater humoral and cellular immunoresponses after the second dose (a much lower intra-dose response was also seen). They also noted an improved response with a longer intra-dose interval. Lower anti-vector immunity was observed post-first-dose, which may contribute to the enhanced effect by increasing the half-life of second-exposure antigen in the body.
Summary of SARS-CoV-2-specific antibody responses in sera of mice treated with either a LD (low dose) or SD (standard dose) prime dose and a SD boost dose 4 weeks later. Summary of SARS-CoV-2-specific CD8+ T cell responses in PBMCs. Effect of extending the prime-boost interval on CD8+ T cells and antibody responses.
They speculate that the first dose may briefly leave the vaccinee more susceptible to infection, but this needs further investigation. The observations may also provide some insight into the mechanisms underlying hybrid immunity.

This is, in essence, rediscovery of similar observations in the original AstraZeneca trials wherein one arm was mistakenly under-dosed resulting in a more complex analysis of low-dose/standard-dose plus standard-dose/standard-dose trial participants and the discovery that the former subsequently exhibited higher antibody immunity titres. Reduced-first-dose regimens may offer more durable, broader, improved immunoresponse, reduce incidences of adverse reactions and provide dose sparing.
DOI: 10.1126/sciimmunol.abi8635.
 
Pfizer/BioNTech have submitted dosing/reactogenicity/immunogenicity data to the FDA for EUA consideration of a two dose 10µg BNT162b2 for 5-11 year olds (dosing interval 21 days).

At 10µg adverse reactions are very low (compared to a standard dose 30µg regimen); they are almost comparable to the placebo arm. The lower dose was observed to induce better neutralising titres than the standard dose. Efficacy to any delta/B.1.617.2 infection, one week after second dose, was 90.7% (95%CI:67.7-98.3).
 
A lower dose of the Vaccine, works better and less side effects than the normal dose in Young uns?
 
Shouldn't be too surprising that there are less side effects.

Both dose levels were pretty much comparable in the immunobridging phase (when they were using immunological data to pick the optimum dosage) - the lower dose just slightly better than the standard dose. Efficacy (the next phase) was then only studied for the lower 10µg dose as that is the one that offered the lowest reactogenicity for the highest immunogenicity.

Essentially the 10µg dose is more than sufficient from an immunological point of view and offers a very low adverse reaction rate.
 
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