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COVID Vaccines in India -A Medical Milestone: Current and Future Prospects

Authors:
  • Dr Varsha's Health Solutions

Abstract

At the start of 2021, two COVID vaccines have received approval for emergency use in India. The review of study data available on the safety and efficacy of these vaccines, and understanding their technological development along with rational of their approval, can help in achievement of a more effective vaccination drive. It is important at this stage that apprehensions and concerns on these vaccines are addressed scientifically in a balanced manner to improve vaccination coverage and success. A peek into what the near future holds also points towards India emerging as an effective global player in vaccines.
Editorial
The Indian Practitioner d Vol.74 No.1 January 2021
7
COVID Vaccines in India – A Medical Milestone:
Current and Future Prospects
Dr. Varsha Narayanan *
* Consultant Family Medicine and Holistic Health, Dr Varsha’s Health Solutions,
Mumbai. Email: info@drvarsha.com.
Abstract
At the start of 2021, two COVID vaccines have received approval for emergency use in India. The review of study data avail-
able on the safety and ecacy of these vaccines, and understanding their technological development along with rational of
their approval, can help in achievement of a more eective vaccination drive. It is important at this stage that apprehensions
and concerns on these vaccines are addressed scientically in a balanced manner to improve vaccination coverage and
success. A peek into what the near future holds also points towards India emerging as an eective global player in vaccines.
Keywords: COVID, vaccine, adenoviral vector, inactivated, immunogenicity, safety
Introduction
It is nothing short of a medical wonder that vac-
cines have been developed for Coronavirus Disease
(COVID) in the same year as the global pandemic
itself. India has received emergency use authoriza-
tion for two COVID vaccines at the start of 2021: The
adenovirus-vector vaccine from Oxford University
and Astra Zeneca UK, being manufactured in India
by Serum Institute, Pune as COVISHIELD, and the
indigenous inactivated vaccine COVAXIN by Bharat
Biotech, Hyderabad with Indian Council of Medical
Research (ICMR) and National Institute of Virology
(NIV).[1] While this undoubtedly represents the re-
lentless development and glory of medical science for
India, there have also been several voices of apprehen-
sion and concern which need appropriate addressing
as well as more data. However, reviewing the current
clinical data available in public domain itself can con-
siderably lay to rest some of the concerns, help in in-
formed decision making, and play a reassuring role in
the successful vaccination drive for India.
COVISHIELD
This is the vaccine being manufactured in India by
Serum Institute, Pune and is the chimpanzee adeno-
virus-vector (ChAdOx1 nCoV-19) vaccine expressing
the SARS-CoV-2 spike protein, developed by Oxford
University and Astra Zeneca UK, called AZ1222. The
data from phase 2 and 3 trials are peer reviewed and
published in public domain. These studies used the
meningococcal vaccine (MenACWY) as control.
The phase 2 study was conducted across 5 sites in
UK with 1077 healthy adults aged 18-55 years (543 re-
ceived ChAdOx1 nCoV-19 vaccine as a single dose of
5 × 10¹⁰ viral particles, 0.5ml intramuscularly, while
the rest received the control vaccine).[2] There were
protocol amendments of introducing prophylactic
paracetamol in 2 of the sites, and 10 participants being
assigned to a 2nd dose after 4 weeks. In the ChAdOx1
nCoV-19 group, spike-specic T-cell responses were
seen to peak on day 14, and anti-spike IgG increased
by day 28 (even further with the 2nd dose). Neutralizing
antibody responses against SARS-CoV-2 evaluated by
both plaque-reduction neutralization test (PRNT50)
and microneutralization assay (MNA80), were detect-
ed in 100% and 91% respectively on day 28 post sin-
gle dose, and 100% (MNA80) on day 42 in the 2-dose
group.
The Indian Practitioner d Vol.74 No.1 January 2021
Editorial
8
Another phase 2 data set of 560 participants was
thereafter released with 160 participants aged 18–55
years (100 in ChAdOx1 nCoV-19 group), 160 aged 56–
69 years (120 in ChAdOx1 nCoV-19 group), and 240
aged ≥70 years (200 in ChAdOx1 nCoV-19 group).
[3] The 2-dose regimen was studied in the 18-55 years
ChAdOx1 nCoV-19 groups (as the single dose regimen
had already been evaluated in the rst phase 2 study in
this age group) while in the >55 years age groups, both
single dose and 2-dose regimens in a 1:1 ratio were
studied. In all 2-dose regimen ChAdOx1 nCoV-19
groups, low (half) dose-standard dose as well as the
standard dose-standard dose regimens were evalu-
ated. This study conrmed that antibody responses
against the SARS-CoV-2 spike protein were induced in
all age groups (including ≥70 years) and were further
increased and maintained at 28 days after the 2nd dose
of vaccination. Cellular immune responses were also
induced in all age and dose groups, peaking at day 14
after vaccination. Within each age group, no signicant
dierences were seen in neutralization antibody titers
between low-dose and standard-dose vaccine recipi-
ents which were achieved by 14 days post 2nd dose in
>99% participants (MNA80).
Local and systemic reactions were seen in 60-80%
participants in the ChAdOx1 nCoV-19 group (20-30%
higher than the control arm), which were reduced by
10-15% by using prophylactic paracetamol.[2] Local
side eects were mainly injection site pain-tender-
ness of mild to moderate intensity. Systemic reactions
were mainly fatigue and headache, along with mus-
cle aches, malaise and fever, with the intensity being
highest in rst 24 hours post injection and resolution
thereafter. Local and systemic reactions were report-
ed in 88% and 86%, 73% and 77%, and 61% and 65% in
the 18–55 years, 56–69 years and ≥70 years age groups
respectively, thereby displaying reduced reactogenic-
ity in the elderly.[3] Among 13 serious adverse events
occurring during the study period, none were vaccine
related.
The phase 3 study has been conducted across 40,000
adult (≥18 years) participants in UK, Brazil and South
Africa, with the data of 11,636 (ChAdOx1 nCoV-19
group + MenACWY control group) published in
peer reviewed public domain.[4] Participants in the
ChAdOx1 nCoV-19 group received two doses contain-
ing 5 × 10¹⁰ viral particles, 0.5ml intramuscularly (stan-
dard dose; SD/SD group; N=4440: 2377 UK and 2063
Brazil), while a subset received half (low) 1st dose and
standard 2nd dose (LD/SD group; N=1367 UK). The 2nd
dose was given from 4-12 weeks apart. Ecacy was
assessed based on non-occurrence of symptomatic
COVID-19 in seronegative participants (with nucleic
acid amplication test-positive swab) after 14 days of
the 2nd dose.
Ecacy was seen to be 62.1% (SD-SD group) and
90% (LD-SD group) with overall ecacy of 70.4%.
Symptomatic COVID infections were seen to occur in
0.5% vs 1.7% in the vaccine vs control group (0.2% vs
2.2% in LD-SD group; 0.6% vs 1.6% in SD-SD group).
While the control group had 10 and 2 cases of hospi-
talized and severe COVID respectively (with 1 death)
>21 days post 1st dose, none such cases were seen in
the ChAdOx1 nCoV-19 vaccine group. The regulato-
ry approval for emergency use in UK has been giv-
en to the SD-SD dosing regimen which had satisfac-
tory safety, ecacy (>50%), immunogenicity, sample
size and age-group representation. The LD-SD group
had inadequate sample size as well as absence of par-
ticipants >55 years (10-12% in SD-SD group). The rate
of serious adverse events was 0.7% in the ChAdOx1
nCoV-19 group (vs 0.8% in MenACWY control group).
There were 3 cases of transverse myelitis reported in
ChAdOx1 nCoV-19 group with only one case conclud-
ed as vaccine related, 14 days after the 2nd dose.
A bridging (phase 2/3) observer-blind random-
ized control immunogenicity-safety study has been
performed in India across 14 centers in 1600 healthy
adults ≥18 years.[5] 400 of these participants are in the
group receiving COVISHIELD or ChAdOx1 nCoV-19
by Oxford-Astra Zeneca in a 3:1 ratio to assess immu-
nogenicity. The remaining 1200 are in the group re-
ceiving COVISHIELD or placebo in a 3:1 ratio to assess
safety. Dosage regimen is the recommended 0.5ml in-
tramuscularly 28 days apart. The recruitment for the
study was completed in November 2020, and the re-
sults are not yet in public domain as on mid-January
2021. This data is being awaited as it can shed light on
how COVISHIELD fares in India in terms of safety-tol-
erance and immunogenicity, even though the same has
been conrmed in global trials.
COVAXIN
Among the conventional technology vaccines,
India’s indigenous vaccine COVAXIN (BBV152 in
clinical trials), is a result of the collaborative eect of
Bharat Biotech-ICMR-NIV. It is a whole-virion vac-
cine consisting of the killed-inactivated NIV-2020-770
SARS-CoV-2 strain isolated from a COVID-19 patient,
sequenced at ICMR-NIV and manufactured at Bharat
Biotech’s Bio-safety level 3 facilities. It is produced in
Vero cell lines and is formulated with a Toll-like re-
Editorial
The Indian Practitioner d Vol.74 No.1 January 2021
9
ceptor 7/8 agonist molecule (IMDG) adsorbed to alum
(Algel). The results of phase 1 and phase 2 clinical trials
are in public domain but awaiting peer review.
The phase 1 was a double-blind randomized con-
trolled study to evaluate the safety and immunoge-
nicity in 375 volunteers (100 each in the 3ug and 6ug
dose Algel-IMDG arms, 100 in the 6ug dose Algel only
arm, and 75 in the Algel only control arm) as a 2-dose
intramuscular injection (0.5ml/dose) regimen, given
2 weeks apart.[6] While majority of trial participants
showed no reaction, some had mild events with all
showing resolution. Immune response with both neu-
tralizing antibodies (anti-IgG S1) and Th-1 cell mediat-
ed response was detected.
The phase 2 was carried out as a double-blind, ran-
domized, multicenter trial with both 3ug and 6ug
Algel-IMDG formulations, given as 2 doses 4 weeks
apart, in 380 patients (12-65 years: 190 per dosage arm).
[7] The corresponding phase 1 participants in the 3ug
and 6ug trial arms (100 each) were also followed up.
The primary outcome of seroconversion (≥4-fold above
baseline rates of neutralizing antibodies, 4 weeks af-
ter the 2nd dose were as follows: 3 ug - 92.9% (PRNT50)
and 88% (MNA50); 6 ug - 98.3% (PRNT50) and 96.6%
(MNA50). No signicant dierences were observed
in seroconversion rates (SCR) or geometrical mean ti-
ters (GMTs) across the three age groups of 12-18, 18-55
and 55-65 years, and for both spike S1 protein- recep-
tor-binding domain RBD, and nucleocapsid N protein
of SARS-CoV-2. The GMTs were 2-fold greater than
seen in corresponding phase 1 trial arms, with the par-
ticipants showing seroconversion rates of 73.5%, and
81.1% (MNA50) for the 3µg and 6ug groups respec-
tively 3 months post 2nd dose. There was also a signif-
icant increase in Th1-biased cytokines, such as IFN-γ,
IL-2 and TNF-α on day 56, suggesting a robust cell me-
diated immune response as well.
Apart from this vaccine showing high rates of im-
munogenicity in phase 1/2, there is also satisfactory ev-
idence of safety and tolerance, with an overall reaction
rate of around 10% after each dose (4% local and 6%
systemic reactions) and no serious adverse reactions
after 2 vaccine doses. Local adverse eects were pain,
itching, redness, or stiness/weakness in injected arm,
while systemic ones included fever, headache, body
ache, and malaise/weakness. These are similar to reac-
tions seen with all vaccines, and were mild to moder-
ate, with most resolving in 24 hours. There was no dif-
ference in the rates between the rst/second dose, or
between the 3/6ug dose.
The 6µg Algel-IMDG-induced responses were
comparable to those observed in convalescent se-
rum collected from patients who had recovered from
COVID-19, and this formulation has been taken ahead
for phase 3 trials, and also given conditional approv-
al for emergency use. The phase 3 multicentric trial is
underway with recruitment completed at 25,800, with
most of them having received the 1st dose, and >5000
of them having also received the 2nd dose without re-
ports of any signicant adverse events.[8] The nal e-
cacy data related to COVID prevention post 2 doses, is
expected in March-April 2021.
The regulatory emergency approval for COVAXIN
(given in the form of a clinical trial mode) before phase
3 completion has raised concerns. The aspects to be
considered here are rstly that India being one of the
largest population segments of the world would re-
quire an unprecedented manufacturing of vaccine
dosages which can be best achieved with development
of more than one vaccine. Secondly COVAXIN has
shown both high immunogenicity in phase 2, which
is considered a surrogate marker of vaccine ecacy,
as well as high safety in both phase 2 and initial phase
3 studies of almost 25,000 patients.[1,7,8] The generation
of data that actually conrms not geing a disease as
the ecacy end point requires long term study in very
large populations, which could be a crucial factor in
the control of an ongoing pandemic. The New Drugs
and Clinical Trials Rules 2019 has the provision for in-
vestigational drugs for unmet medical needs of serious
Vaccine Immuno-
genicity
Local
Reactions
Systemic
Reactions
Serious
vaccine
related
reactions
COVAXIN 96.6-98.3% 3.5-4.5% 5.5-7.5% None
AD1222 99-100% 61-88% 65-86% None
Table 1: Phase 2 results for COVAXIN and AD1222
(manufactured as COVISHIELD, India)
COVAXIN (BBV152: 6ug Algel-IMDG) and AD1222 (ChAdOx1 nCoV-19 as 5 ×
10¹0 viral particles) was given as 0.5ml muscularly, two doses 4 weeks apart.
Immunogenicity for COVAXIN was assessed by Seroconversion rate (SCR)
dened as ≥4-fold above baseline rates of neutralizing antibodies evaluated
by plaque-reduction neutralization test (PRNT50) and microneutralization as-
say (MNA50) at 28 days post 2nd dose.
Immunogenicity for ChAdOx1 nCoV-19 was assessed by PRNT50 assay,
which determined the extent to which serum can be diluted and still reduce
SARS-CoV-2 plaque formation by 50% at day 28, and MNA80 assay, with titers
inducing 80% virus neutralization.
Local reactions are those at injection site mainly pain-tenderness, and sys-
temic reactions include fever, headache, body ache, and malaise. For Covaxin
local (4.2%-1st dose; 3.7%-2nd dose) and systemic (7.4%-1st dose; 5.8%-2nd
dose) reaction rate was similar after the 1st and 2nd dose.
The Indian Practitioner d Vol.74 No.1 January 2021
Editorial
and life-threatening diseases in the country to be ap-
proved based on remarkable phase 2 data with a de-
nite dose, along with a continuation of studies to veri-
fy clinical benets in larger populations.[9] Thirdly, due
to the presence of multiple antigens including the less
variable N protein present in a whole virus inactivat-
ed vaccine, the theoretical possibility of a back-up for
variant strains has been considered.[10,11] Therefore, in
the light of these points, the emergency conditional au-
thorization of this vaccine may be of potential benet
in the success of the vaccination drive in India.
Authorized Vaccines in Other Countries
The ecacy rates of mRNA COVID vaccines, from
Pzer/BioNTech and Moderna, reported in peer re-
viewed publications, has been high at 95% and 94.1%
respectively.[12,13] Given their more stringent storage
temperature requirements (compared to the regular
refrigerator 2-8 deg C storage of the adenoviral-vec-
tor and inactivated vaccines), and absence of initiating
bridging studies in India may preclude their availabil-
ity anytime soon, however several Indians are receiv-
ing the same in the countries of approval like USA, UK
and Canada. Also, discussion for collaborations and
studies for bringing the mRNA vaccines from Pzer
and Moderna to India are still ongoing and a future
possibility.
SPUTNIK V Adenoviral (Ad26/5) vector vaccine
authorized in Russia and developed by the Gamaleya
National Research Center for Epidemiology and
Microbiology of the Ministry of Health of the Russian
Federation has shown an ecacy of 91.4%, based on
the second interim analysis of data obtained 28 days
after administering the 1st dose (7 days after the 2nd
dose). The preliminary data from volunteers obtained
42 days post 1st dose (21 days post 2nd dose) is indi-
cating >95% ecacy without any unexpected adverse
events.[14] While this data is awaiting peer review, this
vaccine is being developed and undergoing clinical
trials in India in collaboration with Dr Reddy’s Labs
(DRL), and is being expected later in 2021.
The results of the completed Phase 3 study across
60,000 volunteers of Sinopharm’s inactivated
vaccine (approved in China and UAE where al-
ready in regular use), published in a press re-
lease (not yet peer reviewed) has claimed an ef-
cacy of around 79% in China and 86% in the
UAE.[15] Again, the inactivated vaccines from
China would not be expected in India given the
availability of its own indigenous inactivated
vaccine.
Future Prospects
So far from existing data of recovering patients as
well as vaccine trial extrapolations, duration of con-
ferred immunity with COVID vaccines stands at
around at least 6 months with the cell mediated immu-
nity expected to last longer than the humoral compo-
nent.[16] India is initiating its vaccination drive starting
with health care and front-line workers, elderly and
those with comorbidities or risks, and thereafter the
general adult population.
There are several vaccines in the pipeline global-
ly and in India.[17] Apart from Sputnik V (with DRL),
Cadila Healthcare has developed a Novel Corona
Virus-2019-nCov-Vaccine using DNA platform tech-
nology and has got approval to conduct phase 3 study
in India.[1]
Conclusion
In all India can look forward to initiating successful
vaccination and control of COVID in 2021 with 2 do-
mestically manufactured vaccines, and also with more
vaccines in the pipeline. The decade ahead for India
promises to be one of medical advancements and dis-
ease control paralleling several developed countries, as
well as emergence as a global player in development
and supply of vaccines.
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10
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... This vaccination aims to immunize 30 crore people. The advent and development of indigenous vaccine and other measures related to the COVID 19 pandemic has proved that India has paralleled developed countries in medical development, medical research and infrastructure [36]. ...
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Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results Download a PDF of the Research Summary. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods Download a PDF of the Research Summary. In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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Background Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. Methods In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 10¹⁰ virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 10¹⁰ virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Findings Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). Interpretation ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
Article
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Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10¹⁰ viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R²=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 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. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
Press Statement by the Drugs Controller General of India (DCGI) on Restricted Emergency approval of COVID-19 virus vaccine
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Covid-19 vaccine: Bharat Biotech completes recruitment for phase 3 trials
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