COVID-19 Vaccine Update

COVID 19 Vaccine update

Prof. Piyush Gupta (President-elect of Indian Academy of Pediatrics)

Talked about WHO target product profile for COVID 19 vaccines

• Efficacy should be 70% on population basis, critical (efficacy with 50% point estimate) and successful vaccines should show disease risk reduction of atleast 50%
• Contraindications should be none except immunocompromised state
• Age covered should be adults and elderly (women and children should be preferred)
• Adverse effects should be only mild and transient adverse effects, no severe AEFI
• Onset of protection should be less than 2 weeks
• Preferred dose should not be more than 2 doses (preferred single)
• Booster may be permitted (lesser the better,min. yearly)
• Time of protection should be 6 months (preferred 1 year)
• Route-Non parenteral oral or nasal preferred (any route, if safe and effective)
• Storage-Higher storage temperature and high thermostability i.e. shell life of atleast 6-12 months at -60, atleast 2 weeks stability at 2-8 C
• Presentation should be multi dose vials and scaling up production at accessible cost

Challenges

Vaccine will be available but how effective it will be is still not clear

Reasons

• Still not sure of the critical levels of antibodies necessary for protection
• Human challenge studies results not available
• Effect at long term not available since it’s too early
• AEF1 and safety will not be known early as the analysis of phase 3 study will take some time
• Still we are not sure about whether viral transmission will reduce as long term data is not available

Prof.Daniel R.Lucey (USA)

USA phase 3 COVID 19 vaccine and new FDA guidelines for EUA

Moderna (with US NIH)

• 30,000 volunteers (15,000 placebo, 15,000 vaccines)
• 2 doses (28 days apart) of mRNA vaccine (no adjuvant)
• Enrolment began 27th July 2020
• Late November: Anticipated date for request to FDA for EUA

PFIZER/BioNtech

• 30,000 volunteers (15,000 vaccine and 15,000 placebo) then requested increase to 44,000 volunteers and age to 16 years old
• 2 doses (21 days apart) of mRNA vaccine (no adjuvant)
• Enrollment began 27 July 2020
• Mid November: Anticipated date for request to FDA for EUA

Johnson and Johnson (J&J)

• 60,000 volunteers in phase 3 study worldwide
• one(1) dose adenovirus 26 vectored vaccine
• Enrolment began 23 September 2020
• Expected-End of 2020:Anticipated date to request FDA EUA
• 6th October 2020:US FDA new guidance for EUA of COVID 19 vaccines

Recent update

• Most important new requirement: longer safety data
• Safety data must be reported after a median of 2 months after the last dose of the vaccine series (2nd dose for Moderna and Pfizer Vaccine, 1 dose for J&J)
• Potential for unanticipated events to occur with the FDA before November 3
• Vaccine companies must themselves first request authorization from FDA

Prof Adam Finn (UK)

Update on UK COVID 19 vaccine trials including ChadOx

Oxford vaccine trial-Adenovirus

• The Oxford vaccine contains the genetic sequence of this surface spike protein. When the vaccine enters cells inside the body, it uses this genetic code to produce the surface spike protein of the coronavirus. This induces an immune response, priming the immune system to attack the coronavirus if it later infects the body
• Cited Lancet study (396467) which showsChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.
  https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2931604-4
• Phase 3 sites: 18 sites in UK, 12330 adults 18+ years old
• RCT1:1 chAdOx vs MenACWYcj 2 doses, started 28th May -nearly fully recruited
• Primary endpoint-symptomatic PCR plus COVID 19
• Secondary endpoints-severe disease, safety, immunology, infection
• Talked about UK 2nd wave with daily 13,864 cases in hospital-3,660 .Interim analysis 15 cases i.e. soon primary endpoint 30 cases
• Talked about Vaccine task force (National institute of health research) which includes-series of trials of other vaccines, one trial recruiting, several in set up, range of vaccine platform s including vectors, recombinant protein and whole inactivated virus vaccines, new sites in setup across UK

Prof.Vinod Paul (Niti Aayog, GOI)

• Talked about vaccine landscape in India that we as a country are present at the forefront in vaccine race for COVID 19
• We are the leaders in supply and manufacture with supply of 2/3rd of vaccine for children globally and also develops original vaccines from our industry
• We have a very strong science and technology, R&D ecosystem, excellent labs, biotechnology and our CSIR to name who can contribute towards developing vaccines
• One of our WHO designated lab DBT has AMTZ Mobile Diagnostic Unit for Covid Testing- I-Lab
• From the academia and technology there are 3-4 vaccines candidates in future pipeline
• Most substantive is that 3 candidates relates to clinical trials and 2 are indigenous vaccines
• Firstly we have ICMR vaccine-killed or inactivated virus vaccine developed at NIV in partnership with Bharat biotech and is called COVAXIN which is in phase 2 trials to be completed very soon and results in 4 weeks’ time and then we move to phase 3 trials and if need be EUA.Large animal assays are done in NIV
• Secondly indigenous vaccine is Cadila zydus vaccine which have used unique DNA platform to develop vaccine for COVID 19.This vaccine is in phase 2 with results awaited in 4-5 weeks then further move to phase 3
• Thirdly we have Oxford vaccine which is in Phase 3trials.it is already being manufactured in India and stockpiled developed. Even as phase 3 trials around 17 cities and on about 1600 Indians are currently going on .Results by Nov. end or by Mid-December
• Serum institute has a huge capacity to stockpile and global distribution depends on it to some extend around 200 million doses (globally and in India)
• Russian Sputnik 5 vaccine colleagues are looking forward for manufacturing and testing trials in India
• 6 other companies are in various stages of negotiation with other partners globally to develop future vaccines
• Additional candidates by serum institute, Bharat biotech and Cadilla are also in pipeline
• Lastly in parallel with these developments the GOI is taking all steps to identify priority groups who should be given vaccine in phase 1 -going forward in 6-8 months and also to ensure how this is to be distributed ,how to identify people using aadhar system, using strong digital platform for capacity ,logistics, vaccine campaigns are in track
• Limited availability is unfolding and plan for large scale production
• India would be seen as a country which will be making vaccine for us but for the world

Dr.Shyam Kukreja (India)

Chinese COVID 19 vaccines

• There are 35 candidates in clinical evaluation, 9 vaccines in phase 3 trials with 4 from China in Phase 3

Timelines-4 Chinese vaccines

• Clinical trials started-April (March) 2020
• Phase1/2 trials results unveiled in June
• Authorized for Emergency use in July
• 4 vaccines-the final stages of clinical trials
• Vaccines could be ready for general public in November/December
• Four candidates are-Sinovac biotech (inactivated)-Coronavac, China National Biotec group (CNBG)-Sinopharm-2 candidates and CanSino Biologics (Adenovirus vector based)-by Chinese biopharm firm with research institute of academy Military science

Sinovac (CoronVac) phase 2 clinical trials

• A total of 600 healthy adults aged 18-59 years were included in the study
• Future Phase 3 clinical trials-low dose-3 mcg vaccine, 2 doses schedule, day 0, 28 days would be adopted
• Another trial involved a total of 421 healthy adult volunteers aged between 60 and 89 years
• The seroconversion rate and GMT were 98% and 42.2, respectively, in elderly volunteers and 97.4% and 44.1 in healthy adults
• Immunogenecity-elicting 92% seroconversion at lower dose
• Phase 3 trial of Corona Vac-More than 24,000 people currently participating in phase 3 clinical trials of CoronaVac in Brazil, Turkey and Indonesia ,with additional trials scheduled for Bangladesh and possibly Chile(according to YIN CEO SinoVac)
• Sinovac’ s Covid 19 vaccine candidate get emergency approval in China-the vaccine not yet passed phase 3 clinical trials, already injected thousands of people in China(including Frontline medical workers)under an emergency use provision 90% of the Sinovac company’s staff(around 3000) have received it
• Stringent regulations in the US, European union, Japan and Australia have historically blocked the sale of Chinese vaccines
• SinoVac plans to apply to the US FDA to sell CoronaVac in the US after phase 3 trials
• Brazil Plans to start immunize its population in mid-December and Indonesia by March 2021 pending regulatory approval
• China’s Sinovac plans to test COVID vaccine on children before the company is sure the inoculation works in adults
• China National Biotec Group(CNBG)-Sinopharm-2 vaccine candidates in phase 3(48000)-first is Wuhan Institute of Biological products-Phase 3 trials launched in UAE,Peru and Morocco(July/Aug),the UAE-15000 participants aged 18 to 60 years to enroll in phase3
• Beijing Institute of biologigal products-Phase 3 trials in the UAE, Bahrain, Jordan and Argentina
• Approved for the emergency use program (without identifying the specific products)
• On Sep 14, The UAE gave emergency approval for Sinopharm’s vaccine to use on health care workers following successful interim results in the phase 3
• CanSino started phase 2 trials in April 12 and on 25th June authorized for military use and on 16th Aug. granted the first invention patent by Chinese authorities. Phase 3 clinical trials overseas in Saudi Arabia, Pakistan and Russia.
• Seroconversion of binding antibody in 96% and 97% of participants, Peer reviewed phase 2 data showing that it can generate antibody and T cell responses

Ad5-nCOV the phase 3 programme

• Phase 3 trials of Ad5-nCoV include Russia, Saudi Arabia, Pakistan, Brazil, Chile, and, with expected to recruit around 40,000 subjects
• China’s Central Military Commission approved the use of the vaccine (EUA)by the military on June 25 for a period of one year

Concerns

• Preexisting Abs. against the common cold virus might undermine efficacy of Ad5-nCoV
• One dose strategy may not work
• Development timelines are slipping
• Inactivated vaccine-Ab -dependent enhancement (ADE) can be induced when the strength of Ab-Ag interaction is below the certain threshold. This Phenomenon might lead to both increased virus infectivity and virulence

Prof.Ashok Dutta (India)

Russian Sputnik 5 vaccine

• Developed by Gamaleya research institute of Epidemiology and microbiology
• Two types of vaccines-Adenovirus 26 and adenovirus 5
• Two Formulation-Frozen and Lyophilized forms
• Phase 1 and phase 2 trials in Russia itself
• Taken very small no. of cases in both phase 1 and phase 2(76 cases), 38 in each phase
• Following phase 2 results published in lancet they have revealed that Ab. titre is very good against the spike proteins, CD4 and CD8 count with both forms has increased and based on that it is used for general use
• Now started phase 3 trials with 40,000 subjects. They have given the name sputnik 5 and Russian direct investment firm in collaboration with dr reddy’s labs in India, a protocol has been submitted to CDSO and the protocol refers some modifications and initially they wanted to do phase 3 trials
• Now phase 1 and phase 2 trials will start and Russian investment development fund committed that they will be providing 100 million doses of vaccines in India
• They have 2 doses-21 days apart
• Antibody titers after 28 days have shown cell mediated immunity is good.
• Another DNA based Russian vaccine developed by Siberian Institute is in phase 2 trials and going to phase 3 trials

Prof.Soumya Swaminathan (Chief Scientist and Deputy DG for Progammes, WHO)

WHO view point-

• In January WHO convened global research forum which looked not only at vaccines, diagnostics and therapeutics but also at the number of different areas for virus containment
• We developed Research road map with 9 different watching group and they started working on epidemiology, source of virus, infection prevention and control, clinical Mangement
• Formed expert groups in enabling sciences which looks at things like standardizing animal models as the COVID being a new virus there were no known animal models
• WHO look at standardizing laboratory assays, antibody assays and immunological tests
• Started a group which look at designing vaccine trials
• WHO came out with solidarity code protocol and also developed target product profiles and there are 2 kind of target product profiles -vaccines as preventive vaccines and other which can be potentially use as an outbreak vaccine
• WHO started having talks with developers and also maintain landscape on vaccines development updated every week
• we have round about 40 vaccines in clinical trials around the world and 10 are in phase 3 trials .the first 2 are Moderna and oxford started in July and followed by some other candidates including pfzer,johnson,Chinese and Russian vaccines and there are 3 trials of vaccine going on in India
• We are looking at R&D side -we worked with SEBI which are funding the R&D -9 candidates for portfolio and another 9 for late stage of development
• We worked on policy so WHO has SAGE which has advisory group of experts on immunization and this SAGE has been functioning for many years and they are the one to develop global guidelines for vaccines
• They setup the working group on COVID vaccines and come up with 2 sets of documents -First is value &preferences that actually explains the principles like equity, justice, reciprocity at both global and national level, equity as principle helps to distribute vaccines because for us the development of vaccine is as important as the equitable allocation
• Second is prioritization framework -countries within themselves how they prioritize to distribute vaccines within population
• First phase approach is who are considered at risk so HCW-Front line workers-geriatric population with comorbidities then accordingly. The definition of older varies country wise like in Japan it is >80 YEARS while in India it is 50-55 years so every country to decide their criteria for the vaccine schedule
• Many countries have formed task force for this and also looking at the supply chain
• Third set of activity WHO focuses is on the regulatory side as we have a system of prequalification of drugs and vaccines and majority of countries around the world(except for major 5-6) rely on WHO prequalified drugs and vaccines
• Last week we have started rolling submission on authorizing vaccines
• Generally a vaccine or drug is post to regulatory authority with a dossier on safety and efficacy and license. In Emergency situation like we are now or in some other kind regulators will look at the data and on interim results and also on safety and efficacy to look at the basic minimum data and when we give EUA
• National regulators have jurisdiction within their own country based on the data they are seeing for use for their own country
• WHO is working with GAVI and SEPI and we have COVAX facility in which many countries have joined including recently China so around 90% have joined (171 countries) and the advantage is that you get to have choice of vaccine, risk pooling in many vaccines and pricing
• Secondly the procurement will be done on large volume so pricing .Self-financing countries (80-85) will actually pay for the vaccine
• We will have GAVI eligible 92 countries which will get vaccine at very low cost or free like 1.5 dollars and low income countries which can’t pay and so we need to increase our resources to 8 billion dollars .The goal of the COVAX is to get 2 billion doses of vaccine by 2021 where there will be supply constraint but in COVAX the countries have vowed for equitable access
• Solidarity trials would test multiple candidates head to head against placebo-we want best vaccine to get, first one may not be best but we want the vaccine to be efficacious, affordable, easy access and good quality vaccine also from trials from India