Las vacunas contra el SARS-COV-2 pueden haber salvado alrededor de 20 millones de vidas. Como todas las estimaciones, el valor exacto puede variar, pero su enorme impacto sobre la salud pública es indiscutible.
COVID-19 vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. However, inadequate access to vaccines in low-income countries has limited the impact in these settings, reinforcing the need for global vaccine equity and coverage.
The first COVID-19 vaccine was delivered outside of a clinical trial setting on Dec 8, 2020.
By Dec 8, 2021, 55·9% of the global population was estimated to have
received at least one dose of a COVID-19 vaccine, 45·5% estimated to
have received two doses, and 4·3% estimated to have received a booster
dose.
Despite the incredible speed with which COVID-19 vaccines were
developed in 2020 and subsequently distributed during 2021, more than
3·5 million deaths due to COVID-19 have been reported globally since the
first vaccine was administered.
Understanding
the global impact of vaccination on the course of the COVID-19 pandemic
is challenging given the heterogeneous access to vaccines coupled with
different levels of transmission and ongoing non-pharmaceutical
interventions across countries. In the early months of 2021, the impact
of vaccination would have been minimal because of the delay in
developing the infrastructure for a widespread vaccination campaign, the
need for a delayed two-dose regimen in some jurisdictions to ensure
maximum protection,
and the delay in the development of antibodies following vaccination.
Additionally, as vaccine supply was constrained, most countries opted to
prioritise vaccination in high-risk populations, including health-care
workers and older people. Such strategies would have generated direct
protection but would have had comparatively less impact on SARS-CoV-2
transmission. However, from mid-2021 onwards those countries with access
to plentiful vaccine supply opted for mass vaccination of the adult
population, later including children and subsequent boosting to maintain
high levels of protection given the waning in vaccine efficacy and the
emergence of new variants of concern. This approach has resulted in vast
inequalities in global vaccine distribution.
To
reduce inequality, a fair allocation mechanism for COVID-19 vaccines
was developed through the COVID-19 Vaccines Global Access (COVAX)
facility, with a key target of achieving 20% vaccine coverage for the
countries covered by its Advance Market Commitment (AMC) through
COVAX-secured doses by the end of 2021.
WHO expanded this target by setting a global strategy to achieve 70%
coverage in all countries by mid-2022, with an interim target of 40%
coverage by the end of 2021.
However, as a result of numerous challenges, particularly the
constrained vaccine supply to COVAX (exacerbated by some countries
obtaining a greater proportion of the global vaccine supply,
pharmaceutical companies not meeting their contractual obligations to
COVAX, and unpredictable delays in supply including vaccines with brief
expiry windows), these targets were not reached in many
lower-middle-income countries and low-income countries. Vaccine uptake has also been suboptimal in many countries because of vaccine hesitancy.
This considerable heterogeneity in vaccination coverage has resulted in
continued reliance on non-pharmaceutical interventions for pandemic
management in some countries but concomitantly enabled other nations to relax interventions as a route out of the pandemic.
Quantifying
the impact of vaccination is further challenged by the incomplete
picture of the COVID-19 pandemic that is obtained from reported deaths.
In many countries, vital registration systems are incomplete and
therefore only a fraction of deaths are routinely reported. However,
even in countries with complete vital registration systems, it is
difficult to accurately define the cause of death in individuals who
present with multiple morbidities. Excess all-cause mortality (the
difference between the observed and expected number of deaths in
non-pandemic years) has therefore been used to quantify the impact of
the COVID-19 pandemic.
Although the exact contribution of COVID-19 to excess mortality is
unknown, the strong temporal correlation observed globally between
reported COVID-19 mortality and excess mortality provides evidence that
excess mortality is an informative indicator of pandemic-related
mortality.
Robust vital registration systems do not exist in many parts of the
world, with WHO estimating that 40% of global deaths that occurred in
2020 were unregistered,
and therefore data on excess mortality are not available for every
country. Model-based estimates have therefore been developed to obtain a
more complete estimate of the pandemic to date. One set of estimates
produced by The Economist uses a range of socioeconomic and epidemiological data to infer excess mortality. Although the precise estimates differ between research groups and WHO, they all suggest a substantially larger number of COVID-19 deaths than have been reported to date.
We
aimed to quantify the global impact of the first year of COVID-19
vaccination and estimate the number of deaths from COVID-19 averted in
185 countries and territories, both from the direct protection of
vaccinated individuals and from the indirect protection of all
individuals living in vaccinated environments due to the reduction in
risk of infection. Additionally, we aimed to quantify the impact that a
more equitable global vaccination campaign, meeting the vaccination
targets set by COVAX of 20% vaccination coverage of the eligible
population by the end of 2021, could have had in COVAX AMC countries. We
also aimed to quantify the impact of achieving the WHO target of 40%
coverage by the end of 2021 in all countries.
Methods
Transmission model fitting
For this mathematical modelling study, we used a previously published COVID-19 transmission model, and fitting framework
to obtain profiles of the COVID-19 pandemic in each country and thus
estimate the counterfactual scenario in which vaccines are not
delivered. Briefly, the model is a population-based, age-structured
susceptible-exposed-infectious-recovered-susceptible (SEIRS) model,
which explicitly captures disease severity, passage through different
indicated health-care levels, and the roll-out of vaccination. We
incorporated country-level data on demography, age-based mixing
patterns, and health-care capacity. We fit the model to officially
reported COVID-19 deaths in each country, resulting in an inferred
time-varying level of transmission, Rt, denoting the
mean number of secondary infections in the absence of both
infection-induced and vaccine-derived immunity. By fitting directly to
mortality, we indirectly captured the impact that non-pharmaceutical
interventions have had over the course of the COVID-19 pandemic.
Vaccination rates for first and second doses in each country were taken from Our World in Data and the WHO dashboard.
We assumed a vaccination strategy that first targets those most at risk
(including health-care workers) and then iteratively distributes
vaccines in descending age order. Vaccination was assumed to confer
protection against SARS-CoV-2 infection and the development of severe
disease requiring hospital admission,
and to reduce transmission from vaccine breakthrough infections (ie, we
assumed vaccinated individuals who develop infection would be less
infectious than unvaccinated individuals).
We inferred vaccine efficacy for each country on the basis of vaccine
types known to be predominantly used in each country. We explicitly
modelled the emergence of the delta (B.1.617.2) variant and its impact
on vaccine efficacy, hospital admissions, and immune escape., Any epidemiological differences associated with previous variants were assumed to be reflected by their effects on mortality, which were subsequently captured by the estimated Rt
trend. We fit the model to COVID-19 mortality in a Bayesian framework
using a Metropolis-Hastings Markov Chain Monte Carlo-based sampling
scheme. We used the resulting fit to estimate the time-varying
reproductive number, Rt, and its associated uncertainty.
Complete details of the model, vaccination, variants, and model fitting are given in the appendix (pp 2–10).
No ethical concerns were noted for this study, with all mortality data
used based on nationally aggregated statistics; all datasets used were
publicly available.
Excess mortality and COVID-19 mortality data
Because
of the heterogeneity in death registration and certification worldwide,
we also fit the model to all-cause excess mortality. For countries and
time periods for which excess mortality had not been reported, we used
model-based estimates of all-cause excess mortality, first produced by The Economist. More details of the methodology are given in the appendix (p 2).
Given the wide uncertainty in these model-based estimates of excess
mortality in many parts of the world, we also presented the deaths
averted as estimated by fitting to official reported COVID-19 deaths
from the Johns Hopkins University COVID-19 Data Repository (appendix p 2).
Importantly, these estimates based on official reported COVID-19 deaths
represent the lower bound of deaths averted at the global level due to
the considerable levels of under-reporting of COVID-19 mortality
documented worldwide.
Estimating deaths averted due to vaccination
The
first vaccination outside a clinical trial setting was given on Dec 8,
2020. We introduced vaccination from this point onwards in the model and
explored the impact of the first year of vaccination up to Dec 8, 2021.
To quantify the impact of vaccination and its associated uncertainty,
we took 100 draws from the estimated distribution of Rt
and vaccine efficacy estimates for each country and simulated a
counterfactual scenario in which no vaccines are available and the
epidemic in each country follows the same Rt trend
since the start of the pandemic; a counterfactual in which vaccines are
delivered but there are no indirect effects (ie, they do not reduce
SARS-CoV-2 transmission); and the observed scenario in which vaccines
were delivered at the rates reported. The third scenario generated an
estimate of the trajectory of the epidemic for our fitted model and
hence closely matched reported COVID-19 or excess deaths or estimated
excess deaths in each country. We calculated the deaths averted as a
result of vaccination by subtracting the estimated COVID-19 deaths from
the simulation with vaccines included (the observed scenario) from the
estimated COVID-19 deaths under the first counterfactual scenario. This
process is illustrated in the appendix (p 18),
which shows the estimated deaths averted for the USA. Because of the
difficulty in predicting how governments and populations would have
responded, and how viral evolution would have progressed if vaccines had
not been available, we made no attempt to adjust the Rt
trends for further non-pharmaceutical interventions, changes in
mobility, or development of variants that probably would have occurred
differently in the absence of vaccination. To explore the impact of key
model parameters on estimates of deaths averted, we did additional
sensitivity analyses. These included characterising the effects of the
assumed relationship between the infection fatality ratio (IFR) and age (appendix p 10), as well as the assumed degree of immune evasion exhibited by the delta variant (appendix p 7).
We
also explored the impact of increasing vaccine distribution to meet WHO
and COVAX targets. We modelled two scenarios in which the targets set
by WHO to fully vaccinate 40% of the eligible population in each country
and administrative region, and by COVAX to fully vaccinate 20% of the
eligible population in AMC countries, by the end of 2021 had been
reached. To do so, for countries in which these targets had not been
met, we scaled the roll-out of vaccines across the year by a constant
factor such that exactly the targeted amount of the population had
received their second vaccine dose by our end date (Dec 8, 2021).
Statistical analysis
All
analyses were done with R software (version 4.1.3), with all data,
code, packages, and versions used available online at GitHub. This
analysis covered 185 countries and territories with a population greater
than 90 000 as reported in World Population Prospects 2019,
and that reported at least one death due to COVID-19 or 1 week of
positive estimated excess mortality. We excluded China from our
estimates because of its unique position as the origin of the detected
epidemic and its large influence on estimates of deaths averted stemming
from its population size.
Role of the funding source
The
sponsors of the study had no role in study design, data collection,
data analysis, data interpretation, or writing of the report.
Results
Based
on our model fit to officially reported COVID-19 deaths, we estimated
that 18·1 million (95% credible interval [CrI] 17·4–19·7) deaths due to
COVID-19 would have occurred without vaccinations worldwide during the
first year of the COVID-19 vaccination programme (Dec 8, 2020, to Dec 8,
2021). Of these, we estimated that vaccination prevented 14·4 million
(95% CrI 13·7–15·9) deaths due to COVID-19, representing a global
reduction of 79% of deaths (14·4 million of 18·1 million) during the
first year of COVID-19 vaccination (table 1). These estimates of vaccine impact do not account for the potential under-ascertainment of deaths related to COVID-19.
Table 1Estimated
deaths averted in the first year of COVID-19 vaccinations worldwide
based on fits to officially reported COVID-19 deaths
| Total COVID-19 deaths | Vaccination coverage (%) | Estimated deaths averted by vaccinations | ||||
|---|---|---|---|---|---|---|
| Total | Per 10 000 people | Per 10 000 vaccines | ||||
| Worldwide | 5 469 000 (5 339 000–5 613 000) | 38·30% | 14 400 000 (13 650 000–15 900 000) | 22·81 (21·63–25·18) | 25·99 (24·64–28·69) | |
| World Bank income group | ||||||
| High-income countries | 1 956 000 (1 892 000–2 032 000) | 68·80% | 6 353 000 (6 105 000–6 604 000) | 52·6 (50·54–54·67) | 36·67 (35·23–38·11) | |
| Upper-middle-income countries | 2 287 000 (2 220 000–2 355 000) | 50·10% | 2 914 000 (2 785 000–3 047 000) | 25·6 (24·47–26·77) | 23·36 (22·33–24·43) | |
| Lower-middle-income countries | 1 188 000 (1 099 000–1 302 000) | 29·80% | 5 083 000 (4 379 000–6 628 000) | 15·27 (13·16–19·91) | 20·39 (17·57–26·59) | |
| Low-income countries | 36 520 (33 390–40 410) | 3·57% | 20 380 (17 680–23 870) | 0·3188 (0·2766–0·3733) | 2·965 (2·572–3·472) | |
| WHO region | ||||||
| African region | 153 800 (145 100–164 700) | 5·48% | 97 190 (88 420–107 400) | 0·8677 (0·7894–0·9589) | 5·958 (5·420–6·584) | |
| Region of the Americas | 2 492 000 (2 418 000–2 576 000) | 58·30% | 3 813 000 (3 624 000–3 987 000) | 37·46 (35·6–39·17) | 29·28 (27·83–30·62) | |
| Eastern Mediterranean region | 318 700 (307 200–331 500) | 28·10% | 639 200 (581 600–707 700) | 8·746 (7·958–9·684) | 13·50 (12·28–14·95) | |
| European region | 1 628 000 (1 589 000–1 673 000) | 56·50% | 4 334 000 (4 214 000–4 487 000) | 46·77 (45·48–48·42) | 39·52 (38·43–40·92) | |
| South-East Asian region | 713 800 (635 900–807 000) | 35·40% | 3 913 000 (3 234 000–5 491 000) | 19·61 (16·21–27·52) | 21·63 (17·88–30·36) | |
| Western Pacific region | 149 000 (120 100–234 400) | 62·40% | 1 574 000 (1 267 000–1 839 000) | 30·14 (24·26–35·21) | 22·58 (18·18–26·38) | |
Deaths
averted are presented as medians with 95% credible intervals, with
values also presented per 10 000 total population and per 10 000
vaccinations (first or second dose). Vaccination coverage is the
proportion of the population with a full dose in the modelled countries
by Dec 8, 2021. Total deaths are all modelled deaths in the presence of
vaccinations when fitted to reported deaths from the start of the
pandemic up to Dec 8, 2021.
Using our model fit to predicted and reported excess mortality (appendix p 23),
we estimated that 31·4 million (95% CrI 30·6–32·1) deaths due to
COVID-19 would have occurred without vaccinations during the first year
of COVID-19 vaccination, with 19·8 million (95% CrI 19·1–20·4) deaths
averted, corresponding to 63% (19·8 million of 31·4 million) of total
deaths (table 2).
The difference between vaccine impact estimates based on excess
mortality and official deaths due to COVID-19 was greatest in low-income
regions, with approximately ten times more deaths estimated to have
been averted in low-income countries when relying on excess mortality
estimates (appendix pp 13, 19).
Using
our model fit to excess mortality, we estimated that most deaths
averted were due to the high levels of individual-level direct
protection conferred by vaccination, with 79% (15·5 million of 19·8
million) of deaths averted through direct protection (figure 1A).
Vaccine impact was also conferred through reducing the levels of burden
placed on health-care systems, reducing the number of days that
health-care capacity would have been exceeded and therefore contributing
to an overall lower fatality rate from infection (appendix p 20).
Throughout 2021, vaccine impact changed over time and space. Vaccine
impact was initially concentrated in lower-middle-income countries (figure 1B),
resulting from the significant epidemic wave in India as the delta
variant emerged. This was subsequently followed by vaccine impact being
concentrated in high-income countries that were then either able to
relax interventions due to high vaccination coverage (eg, the UK), or
that did not implement further restrictions despite the spread of the
more virulent delta variant in the second half of 2021.Table 2Estimated deaths averted in the first year of COVID-19 vaccinations worldwide based on fits to excess mortality
| Total excess deaths | Estimated deaths averted by vaccinations | ||||
|---|---|---|---|---|---|
| Total | Per 10 000 people | Per 10 000 vaccines | |||
| Worldwide | 17 990 000 (17 610 000–18 530 000) | 19 810 000 (19 130 000–20 380 000) | 31·21 (30·14–32·1) | 35·68 (34·47–36·71) | |
| World Bank income group | |||||
| High-income countries | 2 503 000 (2 412 000–2 609 000) | 8 004 000 (7 644 000–8 438 000) | 66·18 (63·20–69·77) | 46·14 (44·07–48·64) | |
| Upper-middle-income countries | 4 717 000 (4 611 000–4 827 000) | 4 230 000 (4 051 000–4 384 000) | 36·97 (35·40–38·31) | 33·71 (32·28–34·94) | |
| Lower-middle-income countries | 9 688 000 (9 329 000–10 170 000) | 7 401 000 (6 841 000–7 655 000) | 22·23 (20·55–23·00) | 29·69 (27·44–30·71) | |
| Low-income countries | 1 087 000 (1 068 000–1 106 000) | 180 300 (171 400–188 900) | 2·711 (2·576–2·840) | 26·23 (24·93–27·48) | |
| WHO region | |||||
| African region | 1 614 000 (1 580 000–1 652 000) | 466 400 (446 300–487 000) | 4·164 (3·985–4·348) | 28·59 (27·36–29·85) | |
| Region of the Americas | 3 354 000 (3 260 000–3 456 000) | 4 469 000 (4 233 000–4 728 000) | 43·89 (41·57–46·43) | 34·31 (32·50–36·29) | |
| Eastern Mediterranean region | 2 310 000 (2 248 000–2 376 000) | 992 800 (938 800–1 066 000) | 13·58 (12·85–14·59) | 20·97 (19·83–22·52) | |
| European region | 3 448 000 (3 347 000–3 568 000) | 5 811 000 (5 551 000–6 187 000) | 62·30 (59·51–66·33) | 52·63 (50·28–56·04) | |
| South-East Asian region | 6 741 000 (6 398 000–7 247 000) | 5 658 000 (5 114 000–5 858 000) | 27·99 (25·3–28·98) | 31·29 (28·28–32·39) | |
| Western Pacific region | 518 700 (489 200–547 800) | 2 429 000 (2 266 000–2 617 000) | 46·31 (43·21–49·91) | 34·74 (32·42–37·44) | |
Deaths
averted are presented as medians with 95% credible intervals, with
values also presented per 10 000 total population and per 10 000
vaccinations (first or second dose). Total deaths are all modelled
deaths in the presence of vaccinations when fitted to excess mortality
from the start of the pandemic up to Dec 8, 2021.
Discussion
The
high individual-level protection against severe disease and mortality
due to COVID-19, as well as the population-level benefit afforded by
mild protection against SARS-CoV-2 infection (before the emergence of
the omicron [B.1.1.529] variant), conferred by vaccination, has
fundamentally altered the course of the COVID-19 pandemic. Directly
measuring the impact of vaccination programmes on COVID-19 mortality is
not possible as the counterfactual (ie, without vaccinations) cannot be
observed. Mathematical models are a valuable tool for quantifying the
impact of vaccination campaigns on epidemic dynamics.
We evaluated the impact of the first year of COVID-19 vaccination,
revealing how vaccinations have more than halved the potential global
death toll due to COVID-19, with an estimated 19·8 million deaths from
COVID-19 averted as a result of vaccination, based on excess mortality
estimates of the impact of the pandemic. These reductions were
concentrated in high-income countries that relied on their vaccination
programmes to relax interventions and allow SARS-CoV-2 transmission to
increase as they moved into a new stage of the pandemic.
In
low-income countries, particularly countries that did not reach the 20%
targets set out by COVAX, vaccine impact was substantially lower, with
vaccine impact estimated to have been almost doubled if the targets had
been reached. If the 40% target, per country, from WHO had been met, we
estimated a further increase in deaths averted, mainly focused in
lower-middle-income countries and low-income countries. A limitation of
our assessment of the COVAX and WHO targets is the timeframe of our
analysis, as these targets were set to be reached by the end of 2021,
whereas our modelling endpoint was Dec 8, 2021, to align with 1 year
since the start of public vaccination. Hence, some countries might have
moved closer to achieving the targets, or achieved them, by the end of
the year. However, any recent vaccination drives would have had
consequently negligible impact given the delay in developing protection
and insufficient impact on COVID-19 dynamics.
Deriving
estimates of vaccine impact is heavily dependent on the counterfactual
scenario chosen. In our counterfactual, we assumed the same time-varying
levels of SARS-CoV-2 transmission as estimated in our model fits.
Consequently, the largest impact was observed in countries that
delivered the most vaccinations to date and simultaneously relaxed
interventions, allowing SARS-CoV-2 transmission to increase. However,
several countries with slower vaccination roll-out as well as countries
adopting a zero-COVID strategy maintained stronger interventions to
suppress transmission and thus observed smaller impacts of their
vaccination programmes as a result. As these countries start to reopen,
we predict that vaccine impact estimates would increase in line with
increasing levels of SARS-CoV-2 transmission.
Under-ascertainment of COVID-19 mortality is a known issue that has hindered our understanding of the pandemic.
In this analysis, we consequently focused on fitting to all-cause
excess mortality, which provides a more complete description of the
pandemic.
However, even when relying on model fits based on reported COVID-19
deaths, we estimated that more than 14 million deaths were averted by
COVID-19 vaccination. The discrepancy between vaccine impact estimates
based on excess mortality and COVID-19 deaths was concentrated in
settings with lower death registration and certification. This
substantial discrepancy underpins the crucial need for continued
investment in civil registration and vital statistics to prevent biases
in mortality reporting further minimising the perceived impact and
necessity of vaccination in settings with lower reporting of deaths. In
countries with more complete reporting systems, our estimates were
broadly comparable to other endeavours focused on officially reported
COVID-19 deaths and on understanding the direct impact of vaccination on
people older than 60 years in Europe.
We identified one study that estimated both the indirect and direct
impact of vaccination, which again yielded estimates for vaccine impact
in the USA that were similar to our impact estimates based on reported
COVID-19 deaths.
In
our effort to provide impact estimates globally, we introduced various
assumptions into our model. We were hindered by the global disparities
in SARS-CoV-2 genomic surveillance and the absence of detailed
vaccination data for the majority of countries. Consequently, key model
inputs had to be created from working assumptions on which vaccines were
delivered, how they were delivered, and when new variants of concern
spread worldwide. We also assumed that the relationship between age and
IFR was the same for each country. These assumptions would have affected
our estimates of deaths averted, with sensitivity analyses showing that
higher overall IFRs will increase the number of deaths that could be
averted by vaccination. Our impact estimates were also limited by the
inherent uncertainty in model-based estimates of excess mortality.
These estimates are likely to have underestimated or overestimated
COVID-19 death tolls in many countries. Notably, our model fits were
unable to recreate excess mortality death tolls in recent epidemic waves
in Iraq and Sudan because of the depletion of the susceptible
population. These discrepancies could have been due to multiple reasons,
including overestimated excess mortality, proportions of excess
mortality not due to COVID-19, higher infection fatality rates by age in low-income settings than those estimated from high-income countries,
and lower vaccine effectiveness than assumed in our framework. Last,
our impact estimates were dependent on the assumed degree of immune
escape that each variant of concern exhibits.
If immune escape was higher than we assumed, more of the population
would have been susceptible to re-infection and consequently more deaths
from COVID-19 could have been averted by vaccination.
More
broadly, our estimates should be considered in light of the
considerable uncertainty inherent in estimating vaccine impact.
Uncertainty in the true death toll of the pandemic, the circulating
variants of concern and their immunological phenotypes, and the vaccines
themselves administered in many countries vastly complicate efforts to
derive accurate estimates of the impact of COVID-19 vaccines. However,
the results of this analysis still provide a comprehensive and thorough
assessment of the impact of COVID-19 vaccination, revealing the
substantial impact that vaccines have had and the millions of lives that
are likely to have been saved during the first year of vaccination.
Despite this, more lives could have been saved if vaccines had been
distributed more rapidly to many parts of the world and if vaccine
uptake could have been strengthened worldwide. Reaching vaccination
coverage targets and improving vaccine coverage globally is dependent on
multiple factors and not solely dependent on improving vaccine
donations.
Vaccine intellectual property needs to be shared more quickly in the
future, with more open technology and knowledge transfer surrounding
vaccine production and allocation. Vaccine distribution and delivery
infrastructure also needs to be scaled up worldwide and misinformation
combatted to improve vaccine demand. Improvements must be made in all
these areas to reach current vaccine targets and help ensure that
vaccines are more equitably distributed in the future.
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00320-6/fulltext
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