WHO and GAVI are coordinating global development and distribution of the Covid-19 vaccine, called COVAX, joined by 156 countries, for delivering two billion doses of the vaccine by end-2021. USA and 38 rich countries, however, will not be a part of this initiative, while China did not clarify its stand on it. On the other hand, in the face of critical reviews by the western scientific community, China and Russia signed a memorandum of understanding for cooperation for vaccine development and other Covid-19 related research activities. The World Bank has decided to allocate $12 billion for the vaccine to the poor countries.
The USA, under ‘Operation Warp Speed’, advanced $8 billion for the Covid-19 vaccine by January 2021. But President Trump is now eager to get it before the November election, from Moderna and Pfizer. Pfizer and BioNTech expect Phase-III data by October, to be followed by an FDA application. But about 60 researchers and bioethicists urged them to compile at least 2 months of safety data first after participants received the second dose. Japan contracted Pfizer for 120 million doses. Canada also signed a contract for the vaccine from USA based manufacturers. Australia has contracted Oxford. The UK asked Novavax to provide 60 million doses.Usual procedures of vaccine development are also being shortened. The UK revised its law to allow vaccination before its licensing, taking a cue from the USA, which issued an emergency use authorization to waive usual restrictions. German CureVac also received regulatory approval from the German Government. But Germany believes a vaccine will not be available before mid-2021, besides its scepticism about the protection and duration. China has already vaccinated plant workers, health workers and armed forces. Some countries in Asia and South America have allowed the Phase-III trial of vaccines from Russia, China, the USA and the UK. Bangladesh has partnered with GAVI and Sinovac.
The total population of the world is about eight billion and since each would require two doses of the vaccine, the need would be about 15-16 billion doses.
Stages of vaccine production
Vaccine development takes six stages- (1) exploratory stage (lasting 2-4 years), (2) pre-clinical stage (testing safety and efficacy in animals), (3) clinical-stage, (4) regulatory review and approval, (5) manufacturing and marketing, and (6) post-marketing quality control by Government. Ten to 15 years are taken to bring a vaccine to the market; for mumps in came in four years- the fastest.
The clinical-stage has three phases- the first, involving 15 to 80 participants, tests safety, type and extent of immunity produced. About 100 to 1,000 people participate in the Phase-II trial, which is randomised and single-blinded, includes those who are at higher risk of acquiring the disease, tests vaccine’s safety, immunogenicity, doses, schedule, and delivery method. Successful Phase-II candidate vaccines move to randomised, controlled, double-blind Phase-III trial involving 30,000 to 80,000 people or more. This phase detects low-frequency side effects that occur one in thousands.
The vaccine approval processIn the USA, the Food and Drug Authority (FDA) follows a multi-step process for approving a vaccine, i.e. (1) application for testing a vaccine; (2) application for a biological license for a clinical trial, followed by the clinical trial; (3) inspection of manufacturing plant; (4) presentation of findings to FDA advisory committee; (5) usability testing of product labeling; (6) post-approval periodic visit to manufacturing plant to oversee production process; (7) monitor the market for safety and effectiveness of the vaccine. The manufacturer may itself conduct market monitoring, which is then called Phase-IV trial. FDA may request the manufacturer to submit its internal test for safety, potency and purity for each lot of vaccine and may also ask to submit samples of each of their product lot. In Bangladesh Directorate General of Drug Administration is the counterpart of the FDA. In the USA CDC also conducts Vaccine Adverse Event Reporting System. It is a passive reporting, often by victims or health care workers. In Bangladesh, IEDCR is the counterpart of the CDC.
Four types of vaccines are being tested: (1) the killed or weakened whole virus; (2) viral Spike protein or its fragment, which the virus uses to enter human cell; (3) transferring part of the viral genome, which codes, e.g. Spike protein, into a different carrier virus which in itself does not cause any notable disease, e.g. adenovirus; and (4) Novavax vaccine which uses its proprietary recombinant protein nanoparticle technology to generate antigens derived from the Spike protein, using patented saponin-based adjuvant Matrix-M, which stimulates the entry of antigen-presenting cells into the injection site and enhance antigen presentation in local lymph nodes.
Vaccines under development
Moderna and NIH of the USA, Johnson and Johnson (and Emergent BioSciences), Novavax, and Pfizer in collaboration with BioNTech of Germany in the USA; Oxford and AstraZeneca (Swedish manufacturer) in the UK; Sinovac with Butantan of Brazil, Sinopharm and Wuhan Institute of Biological Products, and CanSino Biologics and China National Biotec in China; Gamaleya National Research Center for Epidemiology and Microbiology in Russia; CureVac in Germany and Medicago in Canada might market the vaccine by mid-2021.
Oxford and Astrazeneca use chimpanzee adenovirus ChAdOx1 for carrying human nCov-19 to avoid the problems that may accrue from using human adenovirus (HuAd) as a carrier. Adenovirus-supported vaccines were claimed to best produce human T-lymphocyte mediated immunity besides antibody. Being a live virus, it will produce the vaccine comparatively faster. Healthy adults aged 18–55 years and with no laboratory-confirmed Covid-19 infection are administered with vaccine and paracetamol. A booster vaccine is administered 28 days later. The trial vaccine was administered in weakly immune people with no safety problem. Minor side-effects of the vaccine were fatigue and headache. But as noted recently, one volunteer among 8,500 developed some spinal column predicament and the trial was put on hold in the UK and India for some time. Its Phase-III trial recruited 50,000 volunteers in Brazil, the UK, the USA, and South Africa.
Russian Sputnik-V vaccine is the genome of the weakened human adenovirus type 26 (AdHu26) and type 5 (AdHu5), carrying the Spike protein-producing gene of SARS-CoV-2. Two intramuscular doses respectively are administered three weeks apart. Gamaleya National Research Center for Epidemiology and Microbiology, in collaboration with the state-run Russian Direct Investment Fund (RDIF), is developing it. The Phase-III trial is going on in 40,000 people in Saudi Arabia, the UAE, Israel, Brazil and Mexico. Russia claims that 20 countries showed interest in Sputnik-V. Past experiments showed a low booster effect on the AdHu5-carried vaccine due to the induction of neutralizing antibodies to it after the first shot, as an antibody to AdHu5 might exist a priori. This may be as high as 40% in the USA and China and 80% in Africa. Increased adaptive immunity to the AdHu5 vaccine has also been seen reducing antibody response to the carrier adenovirus. Some USA-based scientists emphasize that this vaccine may have only 40% efficacy.
The pre-existing antibody to AdHu5 may, however, be circumvented. Past endeavors to develop AdHu5-based vaccines for HIV and Ebola did not work and inflammatory responses were seen. How the attenuated or weakened AdHu5-carrier virus (in lyophilized and powder form) avoids these, need to be seen. Besides Gamaleya, Russian biopharmaceutical company Petrovax also announced plans on 15 August to launch a Phase-I trial of only an AdHu5-nCoV based vaccine.
To avoid AdHu5 problems, Johnson & Johnson's vaccine uses only AdHu26, a rare strain. The McMaster University of Canada is developing an inhalable AdHu5 vaccine, to circumvent pre-existing immunity. So far the nasal vaccine was not found, however, to stimulate CD8+ T- lymphocytes optimally.
Moderna vaccine injects fat-encapsulated fractions of SARS-CoV-2 mRNA- mRNA1273, into human cells, to produce viral Spike glycoprotein, eliciting antibody against it. The vaccine also produced T-cell response to the SARS-CoV-2 protein in Phase-II. Phase-III will involve 30,000 people from 39 USA states and from Brazil, Argentina, and Germany. Moderna is aiming to seek regulatory review by the FDA as early as in October 2020. CureVac of Germany and Pfizer and BioNTech are also trialling mRNA based vaccines.
USA-based Novavax will enrol 10,000 participants aged between 18 and 84, including racial and ethnic minorities in the UK. The Phase-III trial in the US will enrol 30,000 participants in October. It is undertaking a “mid-stage” vaccine trial in South Africa.
CoronaVac of Sinovac and Butantan is an inactivated vaccine and hence will take longer to produce in bulk but will be safer than the live vaccines. The vaccine produced antibodies to 10 strains of SARS-CoV-2 without severe adverse reactions. The Phase-III recruited 9,000 healthcare professionals in Brazil. Sinovac is also going to conduct the Phase-III trials in Bangladesh (among 4,200 vaccinee and placebo groups), in Turkey and Indonesia. Coronavac will also be tested in children aged 3 to 17 years. Sinovac has already administered the vaccine to 90% of its employees and their family members. Coronavac has produced a better antibody response among older people. In the Phase-II trial, 1 to 3% of the test subjects experienced fever.
China’s state-run company Sinopharm, in collaboration with Wuhan Institute of Biological Products, is trialling an inactivated virus-based vaccine. The study, however, did not measure T cell-mediated responses. Sinopharm launched the Phase-I trial among 15,000 volunteers, aged 18 to 60 years, in the UAE, which has a diverse population of approximately 200 nationalities. It reported no serious adverse effects. It is credited with the first published data from human clinical trials for the Covid-19 vaccine. Sinopharm inoculated medical workers and other high-risk groups since July. Sinopharm is undertaking the Phase-III trials in Peru and Bahrain.
Chinese CanSino Biologics and China National Biotec are trialling AdHu5-nCoV in Brazil, Peru, Chile, Morocco, the UAE, Indonesia and Russia. It is using a weakened version of the adenovirus to carry the Spike protein-producing gene. The Phase-II trials showed the vaccine produces significant immune responses after a single dose. No serious adverse reaction was documented. CanSino became the first company to receive limited approval for the vaccine’s military use. According to the Wall Street Journal, the company is in talks to get emergency approval in several countries before completing large-scale trials.
Volume of production and availability
Moderna hopes to supply 1.3 billion doses of vaccine by end-2021 to the USA. AstraZeneca and Oxford will produce a billion doses of vaccine. Novovax may deliver 2 billion doses by mid-2021. Russia will produce one billion doses for the countries, which it already has MoU with. It will produce 5 million doses by January 2021 and 500 million doses in its five collaborating countries. India’s Reddy’s Laboratory will participate in the Phase-III trial of Sputnik-V after approval from the Indian Council of Medical Research. This will be a joint collaboration with RDIF. In return RDIF will supply one million doses of the vaccine to Reddy’s Laboratory. Reddy’s Laboratory will find a manufacturer in India to produce the vaccine afterwards for up to 300 million doses. The vaccine may be available in the first half of 2021. GAVI and the Bill and Melinda Gates Foundation have funded the Serum Institute of India for 200 million doses.
Sinovac completed a plant in Beijing to produce 300 million doses yearly. The National Health Commission (NHC) expects China’s annual production capacity to reach 610 million doses by end-2020 and is forecasted to reach 1 billion doses per year by end-2021. Sinovac will provide 110,000 free vaccine doses to Bangladesh. It has committed to transfer the technology for production of the vaccine to a qualified Bangladeshi producer at a discounted price. But Sinovac, which expects to manufacture the vaccines in early 2021, will first provide the vaccine to Brazil and Indonesia, since these two countries started the Phase-III trial collaboratively first. Sinovac has agreed to supply 40 million doses to Bio Farma, an Indonesian state-owned company, between November and March.
Funding situation and the price of vaccine
The USA provided $8 billion, including R&D fund, for 300 million doses of the Covid-19 vaccine by January 2021. Moderna got $1.5 billion for the first 100 million doses, costing $25-$30 per dose in the USA, while for other countries it would cost US$32 to US$37 per dose. Pfizer signed a $1.95 billion contract with the USA to provide 100 million doses by December 2020. Pfizer and BioNTech will charge US$ 39 for two doses. Johnson & Johnson and Emergent BioSciences declared their non-profit principle in the pandemic and will sell at US$10 per dose to the US government, which has already provided the manufacturer US$1.0 billion for 100 million doses. The USA will pay other US-based producers and AstraZeneca $4 to $19.5 per dose. The US Government provided $2.1 billion to Sanofi and GlaxoSmithKline for 100 million doses of vaccine and to Novavax, $1.6 billion for vaccine development and mass production. Novavax received $2 billion for its global coronavirus vaccine program.
Oxford University and AstraZeneca say their vaccine will cost about US$4 per dose when sold to the Government. The UK government will buy 60 million doses of the Novavax vaccine. Serum Institute of India will price the Oxford candidate at US$13 for India. But in a recent declaration, it priced US$3 per dose. Sinopharm chief informed, its two-shot regimen will cost around US$145 and is expected to become available in December. CanSino and Sinovac have not announced their price yet.
WHO and GAVI together mastered US$1.4 billion but this amount includes that for research as well. The World Bank will bankroll US$ 12 billion for ensuring the vaccine for poor countries, as a part of its US$ 160 billion coronavirus aid funding. The Bank requested rich countries not to “over-reserve” doses than they would need to release those doses to poorer countries.
Every laboratory that has flow cytometry, the most common cell culture technology based on African green monkey kidney cell line (Vero cell-line) or Rhesus monkey kidney cell line (LLC-MK2), and enzyme-linked immunosorbent assay test facilities, can measure the T-lymphocytes and the titter of neutralizing antibody respectively. These assessments should be done by the government itself, preferably in BSMMU or similar public sector laboratories of repute after four months of the second shot of the vaccine.
The government will have to ensure that it gets the required vaccines in time from its contracted partners at a competitive price without any hiccup. The government will also have to develop an efficient storage and distribution capacity at a much lower temperature, which the present EPI system cannot offer. The amount of vaccine procurement and management capacity should be determined by first assessing the need for the vaccine, based on what percent of people is already immune to Covid-19.
Bangladesh should also race to harness the International Financing Corporation’s $4 billion financing platform to develop vaccines and other essential health products in developing countries.
The writer is a former director, Primary Health Care, and Disease Control, former director of IEDCR, DGHS; former regional adviser of SEARO, WHO and former staff consultant, Asian Development Bank, Bangladesh. He is an epidemiologist.