Comparative epidemiology of ivermectin and vaccines against Delta variant based on real-world data and hypothesized mechanisms of ivermectin immunological action

doi:10.21203/rs.3.rs-1631602/v1

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Research Article

Comparative epidemiology of ivermectin and vaccines against Delta variant based on real-world data and hypothesized mechanisms of ivermectin immunological action

https://doi.org/10.21203/rs.3.rs-1631602/v1

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Purpose

In areas of Africa where ivermectin is widely used as prophylaxis against neglected tropical diseases, COVID-19 morbidity and mortality are markedly lower. Thus, prophylactic administration of ivermectin is expected to be as effective as vaccine administration. This study will evaluate the effect of ivermectin on Delta variant by retrospective comparative epidemiology with vaccines and estimate its mechanism of action.

Methods

We used the 4-month observation period during which Delta variant was prevalent. Vaccine-using countries were divided into two groups according to the presence or absence of an inactivated vaccine approval. The number of confirmed cases, deaths, and recoveries in the ivermectin-using countries and countries with full vaccination coverage of 50% or higher were corrected using adjustment factors calculated from population factors, medical care, and test systems. The median test performed statistical comparisons by adjusted values between the ivermectin group and each vaccine group. Vaccine efficacy rates against ivermectin were calculated based on odds ratios. Spearman's rank correlation coefficient examined the interaction between ivermectin and each vaccine.

Results

Ivermectin was statistically less effective than the non-inactivated vaccines but was not statistically significantly different from the inactivated vaccine-approved group for all items. Vaccine efficacy against ivermectin was 35% for the non-inactivated vaccines and 13% for the inactivated vaccine-approved group. The interaction between ivermectin and the non-inactivated vaccines may reduce morbidity, while the inactivated vaccines may increase morbidity and mortality.

Discussion

Ivermectin may have both chemical actions and immune response mechanisms against SARS-CoV-2. Ivermectin is less effective than the non-inactivated vaccine but is more effective than the inactivated one. When used in combination with a non-activated vaccine, it may further reduce morbidity. The vaccine effect of ivermectin may last approximately 5 months. The vaccine-like effects of ivermectin may activate the retinoic acid-induced gene-I pathway, leading to antibody production and autophagy.

Infectious Diseases

Virology

Immunology

Ivermectin

Vaccine

SARS-CoV-2

Comparative epidemiology

Immune system

The COVID-19 infection, which began in Wuhan at the end of 2019, has spread around the world in a series of mutations and pandemics. Infection and its symptoms can affect multiple organs and cause a variety of immunopathological changes leading to death. Vaccines are essential for the control of COVID-19 infection. However, it is not easy to provide a safe and inexpensive vaccine that everyone can be vaccinated against. Although a reliable treatment has not yet been established, ivermectin has been used as an antiviral drug, but no clear evidence has been presented to prove its efficacy. On the other hand, epidemiological and statistical analyses of the prophylactic use of ivermectin in Africa have shown significantly lower morbidity and mortality from COVID-19 in areas where ivermectin is used prophylactically, compared to areas where it is not [1, 2]. In short, these epidemiological analyses in Africa suggest that ivermectin is as effective as a vaccine.

Vaccines approved for emergency use were successful in controlling epidemics in countries where more than 50% of the population was fully immunized [3]. Recent reports have confirmed that immunity acquired through a full dose of immunization attenuates in about six months [4–6]. It has also been pointed out that the vaccine may be less effective than Delta variant, which is twice as infectious, transmissible, and virulent as the conventional strain and is spreading rapidly in many countries [7–9]. In India and Mexico, however, ivermectin use reduced morbidity and mortality during Delta variant epidemic, even though vaccination rates remained low [10–12].

If ivermectin is as effective as a vaccine, there should be no statistically significant differences in infection rate, mortality rate, infection fatality rate (IFR), and recovery rate between countries where ivermectin is approved or widely used and countries with a full dose vaccination. Comparisons between the two can be obtained from statistical analysis of real epidemiological data adjusted for three factors: population factors, medical care, and test systems.

As of May 2021, mRNA vaccines (Pfizer Biotech, Modela), DNA vaccines, viral vector vaccines (Oxford-AstraZeneca, Johnson & Johnson, Sputnik), inactivated vaccines (Sinopharm, Coronavac, Cobaxin), recombinant protein vaccines, and peptide vaccines by multiple methods and manufacturers, some already started and some in development [13]. WHO has approved mRNA and viral vector vaccines produced in Europe and the United States, as well as inactivated vaccines produced in China. However, the effects of these vaccines are not believed to be the same [14], and results will vary depending on which type of vaccine is used. In other words, the relationship between ivermectin and vaccines can be examined by dividing the two groups according to what vaccines are approved and comparing the epidemiology with countries where ivermectin has been widely adopted.

The purpose of this study is to determine by a retrospective comparative epidemiological analysis whether ivermectin has the same effect as vaccines, and interacts with vaccines, and to estimate the mechanism of its immune action.

A comparative epidemiologic statistical analysis with adjusted values was performed on infection, mortality, infection fatality, and recovery rates between countries where ivermectin was approved and widely used (ivermectin group) and two grouped countries where was at least 50% vaccination. One was approved only for the non-inactivated vaccines (non-inactivated vaccine group), and the other was approved for the inactivated vaccines and used both ones (inactivated vaccine-approved group). According to Our World in Data, during an outbreak of Delta variant, the actual situation was that even countries using the inactivated vaccines were administering the non-inactivated vaccines. The efficacy of ivermectin was examined based on the efficacy rate of the vaccine against ivermectin based on odds ratios. And the interaction between ivermectin and each vaccine group were analyzed.

Study design and Data collection

This comparative epidemiological statistical study used real epidemiological data to examine the efficacy of ivermectin against COVID-19 and each vaccine. The lower limit of vaccination coverage was set at 50% of the value at which herd immunity is obtained when the basic reproductive number (R0) is 2.0 [3]. The observation period was four months from May 1 to August 31, 2021, when Delta variant was globally endemic. Based on these data, we calculated the infection, mortality, infection fatality, and recovery rates per million population for each country. The data on population, life expectancy (LE), ivermectin widely used countries, full COVID-19 vaccination coverage, Healthcare Access and Quality Index (HAQI) and COVID-19 data for each country were obtained from UN population and vital statistics report, our data in the world, ivmmeta.com, COVID-19 Worldometers, and World Health Statistics 2021 [15–19]. Details on the acquisition data were presented in Tables 1–3.

Table 1

More than 50% non-inactivated vaccination in 18 countries (raw data)
Country Population (M)	Confirmed Cases May 1 Aug 31 Change (Infection)	Deaths May 1 Aug 31 Change (Mortality)	Fatality (%)	Recovery (per M)	Full Vaccine Rate (%) LE/HAQI
USA 333.0	33153753 40151528 6997775 (21014.3)	593542 660476 66934 (201.0)	0.96	6930841 (13349.6)	53.0 78.5 / 81.3
Canada 38.1	1227035 1499163 272128 (7142.5)	24261 26932 2671 (70.1)	0.96	269457 (7072.4)	76.0 82.2 / 87.6
UK 67.9	4406931 6789161 2382230 (35292.3)	127560 132535 4975 (73.7)	0.21	2377255 (35218.6)	69.2 81.4 / 84.6
France 65.4	5270938 6765708 1494773 (22855.9)	104709 114491 9782 (149.6)	0.65	1484991 (22706.3)	63.2 82.5 / 87.9
Belgium 11.6	990229 1182810 192581 (16601.8)	24230 25374 1144 (98.6)	0.59	191437 (16503.2)	78.4 81.4 / 87.9
Netherland 17.2	1502107 1941055 438948 (25520.2)	17169 18010 841 (48.9)	0.19	438107 (25471.3)	64.9 81.8 / 89.5
Austria 9.1	620485 688305 67820 (7452.7)	10233 10772 539 (59.2)	0.79	67281 (7393.5)	63.9 81.6/ 88.2
Germany 84.0	3412373 3955418 543045 (6464.8)	83702 92730 9028 (107.5)	1.66	534017 (6357.3)	62.0 81.7 / 86.4
Portugal 10.7	836947 1039492 202545 (18929.4)	16976 17743 767 (71.7)	0.38	201778 (1885.6)	72.0 81.6 / 84.5
Spain 46.8	3536986 4855065 1318079 (28164.1)	78742 84340 5598 (19.6)	0.42	1312481 (28044.5)	73.0 83.2 / 89.6
Italy 60.4	4035165 4539984 504819 (8357.9)	121126 129259 8133 (134.6)	1.61	496686 (8223.3)	61.9 83.0 / 88.7
Poland 37.8	2798621 2888670 90049 (2382.2)	67924 75345 7421 (196.3)	8.24	82628 (2185.9)	50.0 78.3 / 79.6
Greece 10.4	346422 587964 241542 (23225.2)	10453 13622 3169 (304.7)	1.30	228373 (22920.5)	56.0 81.1 / 87.0
Denmark 5.8	252045 345693 93648 (16146.2)	2489 2584 95 (16.3)	0.10	93553 (16129.8)	57.0 81.3 / 85.7
Switzerland 8.7	659974 779659 119685 (13756.9)	10633 10993 360 (41.4)	0.30	119325 (13715.5)	72.0 83.4 / 91.8
Sweden 10.1	983585 1127900 144315 (14288.6)	14155 14651 496 (49.1)	0.34	143919 (14239.5)	51.0 82.4 / 90.5
Israel 9.3	838481 1066352 227871 (24502.2)	6363 7043 680 (73.1)	0.30	227191 (24429.1)	63.0 82.6 / 85.5
Ireland 5.0	249437 348993 99556 (19911.2)	4906 5092 186 (37.2)	0.19	99370 (19874.0)	68.0 81.8 / 88.4
Total 831.3	15420409 (18549.8)	122819 (147.7)	0.80	15298690 (18403.3)	63.6 81.7 / 87.5

Table 2

More than 50% of vaccination in 9 inactivated vaccine-approved countries (raw data)
Country Population (M)	Confirmed cases May 1 Aug 31 Change (Infection)	Deaths May 1 Aug 31 Change (Mortality)	Fatality (%)	Recovery (per M)	Full Vaccine Rate (%) LE/ HAQI
Turkey 85.3	4849408 6388331 1538923 (18041.3)	40504 56710 16206 (190.0)	1.05	1522717 (17851.3)	45.0 78.6 / 76.2
Hungary 10.0	781299 812337 31038 (3103.8)	27701 30058 2357 (235.7)	7.59	28681 (2868.1)	56.2 76.2 / 79.6
Seychelles 0.1	6137 19976 13839 (138390)	28 104 76 (760)	0.55	13763 (137630)	70.5 73.3 / 66.1
UAE 10.0	521948 718370 196422 (19642.2)	1591 2041 450 (45.0)	0.23	195972 (19597.2)	76.0 74.3 / 72.2
Chile 19.3	1204755 1638675 433920 (22482.9)	26457 36937 10480 (543.0)	2.41	423440 (21939.9)	71.0 80.2 / 76.0
Uruguay 3.5	200908 384934 285109 (81459.7)	2669 6032 3363 (960.9)	1.18	281746 (80498.9)	72.0 77.1 / 79.6
Mongolia 3.9	37285 213820 176535 (45265.4)	115 937 822 (210.8)	0.47	175703 (45052.0)	63.0 68.1 / 58.5
Bahrain 1.7	177997 272540 94543 (55613.5)	648 1388 740 (435.3)	0.78	93803 (55178.2)	62.0 75.8 / 79.0
Malesia 32.7	411594 1746254 1334660 (40815.3)	1521 16664 15143 (463)	1.13	1319517 (40352.2)	46.5 74.7 / 66.6
Total 166.5	4104989 (24654.6)	49637 (298.1)	1.71	3875342 (23275.3)	62.5 75.4 / 72.6

Table 3

Ivermectin approved 20 countries (raw data) (*Inactivated vaccine-approved country)
Country Population (M)	Confirmed cases May 1 Aug 31 Change (Infection)	Deaths May 1 Aug 31 Change (Mortality)	Fatality (%)	Recovery (per M)	Full Vaccine Rate (%) LE/HAQI
India 1378.6	16549656 2810892 16261236 (11795.5)	218320 439054 220734 (160.1)	1.36	16040502 (11635.3)	10.6 70.9 / 44.8
*Egypt 104.5	228584 288441 59857 (572.8)	13402 16736 3334 (31.9)	5.57	56523 (540.9)	3.0 71.8 / 61.0
Slovakia 5.5	382720 394923 12203 (2218.7)	11732 12548 816 (148.4)	6.68	11387 (2070.4)	39.9 78.2 / 78.6
*North Macedonia 4.7	152367 175624 23257 (4948.3)	4855 5901 1046 (222.5)	4.50	22211 (4725.7)	25.5 74.8 / 76.0
*Belize 0.4	12668 16353 3685 (898.8)	323 362 9 (21.9)	0.24	3676 (8965.8)	17.3 74.4 / 58.3
Bolivia 11.8	305594 490467 184873 (15667.2)	12975 18429 5454 (462.2)	2.95	179419 (15205.0)	23.4 72.1 / 59.2
*Cambodia 16.7	13790 93055 79265 (4746.4)	97 1903 1806 (108.1)	2.28	77459 (4638.3)	50.3 70.1 / 50.7
Guatemala 18.3	228477 470227 241750 (13210.4)	7543 11926 4473 (244.4)	1.85	237277 (12966.0)	6.6 72.0 / 55.7
*Dominica Re 10.8	266561 350017 83456 (7727.4)	3480 4007 527 (48.8)	0.63	82929 (7678.6)	42.5 74.3 / 62.5
*Nicaragua 6.7	6898 11735 4873 (727.3)	182 200 18 (2.7)	0.37	4855 (724.6)	0.7 74.7 / 64.3
Panama 4.3	364884 457487 92603 (21535.6)	6235 7061 826 (192.1)	0.89	91777 (21343.5)	37.3 78.5 / 64.4
Bulgaria 6.9	404846 455742 50896 (7376.2)	16444 18896 2452 (355.4)	4.80	48444 (7020.9)	15.8 75.1 / 71.4
*Venezuela 28.3	198865 335223 136358 (4818.3)	2155 4026 1871 (66.1)	1.37	134487 (4752.2)	11.6 72.1 / 64.7
Honduras 10.0	212333 338757 126424 (12642.4)	5281 8902 3621 (362.1)	2.86	122803 (12280.3)	13.0 75.5 / 53.9
*Bangladesh 166.5	760584 1500648 740064 (4444.8)	11510 26195 14685 (88.2)	1.98	725379 (4356.6)	19.1 72.6 / 51.7
*Mexico 127.6	2344755 3341264 996509 (7809.6)	224488 258491 34003 (266.5)	3.41	962506 (7543.2)	26.3 76.0 / 62.6
South Africa 60.0	1582841 2777659 1194818 (19913.6)	54406 82261 27855 (464.2)	2.33	1166963 (19449.4)	10.0 65.3 / 52.0
*Lebanon 6.8	527508 602266 74758 (10993.8)	7302 8053 751 (110.4)	1.00	74007 (10883.4)	16.1 79.0 / 80.0
*El Salvador 6.5	69198 95782 26584 (4089.8)	2124 2918 794 (122.2)	2.99	25790 (3967.7)	43.3 73.5 / 64.4
*Zimbabwe 15.1	38260 124773 86513 (5729.3)	1568 4419 2851 (188.8)	3.29	83662 (5540.5)	10.8 61.5 / 48.7
Total 1990.0	20479982 (10291.4)	327929 (164.8)	2.57	20152056 (10126.7)	21.15 73.1 / 61.3

Calculation of adjustment factors to correct medical disparities

Depending on the level of medical care, the number of COID-19 tests and the quality of treatment will vary. Mortality rates vary depending on a country's age structure. Countries with a large number of young people have lower mortality rates than countries with a large number of elderly people. Levin et al. reported that the infection fatality ratio (IFR) in developing countries was about twice that of high-income countries [20]. Therefore, it was necessary to adjust the collected data to conform to the same standards. Since the infection fatality rate (IFR) was the ratio of the number of deaths to the number of infection cases, the number of infection cases could be determined from the IFR value and the number of deaths. That is, adjustment for variation in age, level of medical care, and COVID-19 test was fundamental. Age was adjusted from life expectancy (LE), medical level from HAQ index, and the number of tests from IFR.

In determining the number of adjustment factors, the reference values were calculated as follows. Adjustment coefficients were set to be consistent with the average value of developed healthcare countries. First, using the U.S. Healthcare Access and Quality Index (HAQI) of 81.3 as the standard, countries with a value of 81.3 or higher were considered to be medically advanced countries. This was met by 16 countries in the non-inactivated vaccines group (Table 1), excluding Poland. Second, for each item, the average values were calculated from Table 1 for 16 countries with an average non-inactivated vaccine coverage of 64.5%. The average Healthcare Access and Quality Index (HAQI) of 87.4 was used as an indicator of the level of medical care; The standard for correction by age was an average life expectancy (LE) of 82.4 years; An average value of 0.64 was used for correction by the infection fatality rate (IFR). The HAQI adjustment factor was calculated by dividing 87.4 by the country's HAQI value, correcting only for cases below 87.4. If higher than 87.4, the adjustment factor was set to 1. The adjustment factor by life expectancy (LE) was made only when the base value was less than 82.4 years and was calculated by dividing each country's life expectancy (LE) by 82.4. If higher than 82.4, the adjustment factor was set to 1. The adjustment factor from the IFR was calculated only when the reference average IFR was 0.64 or higher, and the IFR of the target country was divided by 0.64 to obtain the adjustment factor. If less than 0.64, an adjustment factor of 1 was used. This adjustment factor was multiplied by the respective values for each country to calculate the correction value.

The adjustment factor (Fx) for each country was using the following formula:

$$Fx=\frac{87.4}{HAQI}X\frac{82.4}{LE}X\frac{IFR}{0.64}$$

$$( HAQI < 87.4, LE < 82.4 and IFR > 0.64 )$$

Table 4 showed the population (in millions), adjusted factor, adjusted infection rate (adjusted number of confirmed cases per million population), adjusted mortality rate (adjusted number of deaths per million population), adjusted infection fatality rate (percentage), adjusted recovery rate (per million population and percentage), life expectancy (LE) and healthcare access and quality index (HAQI) for the 18 non-inactivated vaccinated countries (non-inactivated vaccine group) during the 4-month observation period. The results for the 9 inactivated vaccine-approved and used countries (inactivated vaccine-approved group) were available in Table 5. Table 6 showed 20 countries where ivermectin was widely used with an average of 21% full vaccination (ivermectin group), and the asterisk was the country in which the inactivated vaccines were approved.

Table 4

More than 50% non-inactivated vaccination in 18 countries (Adjusted data)
Country Pop. per Mil. Adj. F.	Corr. Infection Change (Rate per Mil.)	Corr. Mortality Change (Per Mil.)	IFR Recovery Rate (%)	Corr. Recovery Change (Per Mil.)	Full Vaccine Rate (%) LE / HAQI
USA 333.0 1.68	11756262 (35304)	112449 (337.7)	0.96 99	11643813 (22427.3)	53.0 78.5 / 81.3
Canada 38.1 1.50	408192 (10713.8)	4007 (105.2)	0.96 99	404185 (10608.6)	76.0 82.2 / 87.6
UK 67.9 1.00	2382230 (35292.3)	4975 (73.7)	0.21 99.79	2377255 (35218.6)	69.2 81.4 / 84.6
France 65.4 1.00	1494773 (22855.9)	9782 (149.6)	0.65 99.35	1484991 (22706.3)	63.2 82.5 / 87.9
Belgium 11.6 1.00	192581 (16601.8)	1144 (98.6)	0.59 99.4	191437 (16503.2)	78.4 81.4 / 87.9
Netherland 17.2 1.00	438948 (25520.2)	841 (48.9)	0.19 99.8	438107 (25471.3)	64.9 81.8 / 89.5
Austria 9.1 1.23	83419 (9166.8)	663 (72.8)	0.79 99.2	82756 (9094)	63.9 81.6 / 88.2
Germany 84.0 2.59	1406487 (16743.8)	23383 (278.4)	1.66 99.3	1383104 (16465.5)	62.0 81.7 / 86.4
Portugal 10.7 1.00	202545 (18929.4)	767 (71.7)	0.38 99.6	201778 (1885.6)	72.0 81.6 / 84.5
Spain 46.8 1.00	1318079 (28164.1)	5598 (19.6)	0.42 99.58	1312481 (28044.5)	73.0 83.2 / 89.6
Italy 60.4 2.52	1272144 (21061.9)	20495 (339.2)	1.61 98.39	1251649 (20722.7)	61.9 83.0 / 88.7
Poland 37.8 15.00	1350735 (35733.7)	111315 (2944.8)	8.24 91.76	1239420 (32788.5)	50.0 78.3 / 79.6
Greece 10.4 2.03	490330 (47147.1)	6453 (618.5)	1.30 98.7	463597 (22920.5)	56.0 81.1 / 87.0
Denmark 5.8 1.00	93648 (16146.2)	95 (16.3)	0.10 99.9	93553 (16129.8)	57.0 81.3 / 85.7
Switzerland 8.7 1.00	119685 (13756.9)	360 (41.4)	0.30 99.7	119325 (13715.5)	72.0 83.4 / 91.8
Sweden 10.1 1.00	144315 (14288.6)	496 (49.1)	0.34 99.66	143919 (14239.5)	51.0 82.4 / 90.5
Israel 9.3 1.00	227871 (24502.2)	680 (73.1)	0.30 99.7	227191 (24429.1)	63.0 82.6 / 85.5
Ireland 5.0 1.00	99556 (19911.2)	186 (37.2)	0.19 99.8	99370 (19874.0)	68.0 81.8 / 88.4
Total 831.3	23470797 (27403.1)	303668 (365.3)	0.80 98.65	23153931 (27852.7)	63.6 81.7 / 87.5

Table 5

More than 50% of vaccination in 9 inactivated vaccine-approved countries (Adjusted data)
Country Pop. per Mil. Adj. F. Corr.	Corr. Infection Change (Rate per Mil.)	Corr. Mortality Change (Per Mil.)	IFR Recovery rate (%)	Corr. Recovery Change (Per Mil.)	Full Vaccine Rate (%) LE / HAQI
Turkey 85.3 1.91	2939343 (34458.9)	30953 (362.9)	1.05 98.9	2908390 (34096)	45.0 78.6 / 76.2
Hungary 10.0 14.09	437325 (13732.5)	33210 (3321)	7.59 92.4	404115 (40411.5)	56.2 76.2 / 79.6
Seychelles 0.1 1.48	20182 (201820)	112 (1120)	0.55 99.4	20070 (200700)	70.5 73.3 / 66.1
UAE 10.0 1.43	280883 (28088.3)	643 (64.3)	0.23 99.77	280240 (28024)	76.0 74.3 / 72.2
Chile 19.3 4.45	1930944 (100048.9)	46636 (2416.3)	2.41 97.59	1884308 (97632.6)	71.0 80.2 / 76.0
Uruguay 3.5 2.16	615835 (175953)	7264 (2075.5)	1.18 98.8	608571 (173877.6)	72.0 77.1 / 79.6
Mongolia 3.9 1.80	317763 (81477.7)	1480 (378)	0.47 99.53	316283 (8109.7)	63.0 68.1 / 58.5
Bahrain 1.7 2.10	198540 (11688)	1554 (914.1)	0.78 99.2	196986 (115874.2)	62.0 75.8 / 79.0
Malesia 32.7 1.87	2495814 (76324.6)	28317 (865.8)	1.13 98.87	2467497 (75458.6)	46.5 74.7 / 66.6
Total 166.5	9236629 (53865.3)	136995 (822.8)	1.71 95.48	8819220 (52958.3)	62.5 75.4 /72.6

Table 6

IVM approved 20 countries (Adjusted data) (*Inactivated vaccine-approved country)
Country Pop. per Mil. / Adj. F.	Corr. Infection Change (Rate per Mil.)	Corr. Mortality Change (Per Mil.)	IFR Recovery rate (%)	Corr. Recovery Change (Per Mil.)	Full Vaccine Rate (%) LE/HAQI
India 1378.6 4.80	78053932 (56618.4)	1059523 (768.5)	1.36 98.6	76994409 (55849.4)	10.6 70.9 / 44.8
*Egypt 104.5 14.30	855955 (8191)	47676 (456.2)	5.57 94.4	808279 (7734.9)	3.0 71.8 / 61.0
Slovakia 5.5 12.20	148878 (27068.1)	9952 (1710.5)	6.68 93.3	138921 (25258.9)	39.9 78.2 / 78.6
*North Macedonia 4.7 / 8.89	206755 (43990.4)	9299 (1978)	4.50 95.5	197456 (42011.5)	25.5 74.8 / 76.0
*Belize 0.4 1.65	6080 (1483)	15 (37.5)	0.24 99.7	6065 (14793.6)	17.3 74.4 / 58.3
Bolivia 11.8 7.90	1460497 (123770.9)	43087 (3651..4)	2.95 97.0	1417410 (120119.5)	23.4 72.1 / 59.2
*Cambodia 16.7 7.71	611133 (36594.7)	13940 (833.5)	2.28 97.7	597193 (4638.3)	50.3 70.1 / 50.7
Guatemala 18.3 5.17	1249848 (68297.7)	23125 (1263.7)	1.85 98.1	1226723 (67034.0)	6.6 72.0 / 55.7
*Dominica Re 10.8 / 1.56	130191 (12054.7)	822 (76.1)	0.63 99.3	129369 (11978.6)	42.5 74.3 / 62.5
*Nicaragua 6.7 1.20	5848 (872.8)	22 (3.2)	0.37 99.6	5826 (869.5)	0.7 74.7 / 64.3
Panama 4.3 1.78	164833 (38333.4)	1470 (341.9)	0.89 99.1	163363 (37991.4)	37.3 78.5 / 64.4
Bulgaria 6.9 10.06	512014 (74214.6)	24667 (3574.9)	4.80 95.2	487347 (70630.3)	15.8 75.1 / 71.4
*Venezuela 28.3 3.29	448618 (15852.2)	6156 (217.5)	1.37 98.6	442462 (15634.7)	11.6 72.1 / 64.7
Honduras 10.0 7.89	997485 (99748.5)	28570 (2857)	2.86 97.1	968915 (96891.5)	13.0 75.5 / 53.9
*Bangladesh 166.5 5.93	4388580 (26357.8)	87082 (523)	1.98 98.0	4301498 (25834.8)	19.1 72.6 / 51.7
*Mexico 127.6 8.09	8061758 (63179.9)	275084 (2155.8)	3.41 96.6	7786674 (61024.1)	26.3 76.0 / 62.6
South Africa 60.0 9.66	11541942 (192365.7)	269079 (4484.7)	2.33 97.6	11272863 (187881.1)	10.0 65.3 / 52.0
*Lebanon 6.8 1.77	132322 (19459.1)	1329 (195.4)	1.00 99.0	130993 (19263.7)	16.1 79.0 / 80.0
*El Salvador 6.5 7.11	189012 (29078.4)	5645 (868.5)	2.99 97.0	183367 (28210.3)	43.3 73.5 / 64.4
*Zimbabwe 15.1 12.33	1066705 (70642.7)	35153 (2328.0)	3.29 96.67	1031552 (68314.7)	10.8 61.5 / 48.7
Total 1990.0	110230225 (55392)	1915899 (962.8)	2.57 98.24	108290699 (54417.4)	21.2 73.1 / 61.3

Statistical Analysis

All statistical analyses were performed using Microsoft Excel 2010 (Microsoft Corporation Redmond, Washington). Statistical comparisons from the adjusted values between the ivermectin group and each vaccinated group were made using the median test. The vaccine efficacy rate against ivermectin was calculated based on odds ratios obtained from multivariate analysis. Odds ratios and 95% confidence intervals (CIs) for mortality were calculated. The effective rate was estimated as (1 - odds ratio) x 100%. The ivermectin group was examined to see if ivermectin therapy had any effect on the vaccine by using Spearman's rank correlation coefficient from Table 6. Significance was set at p < 0.05.

Figure 1 presented the raw data before adjustment and Fig. 2 showed the data after adjustment. Statistical comparisons between the ivermectin group and each vaccine group were performed by Median Test, and the following results were obtained. Between the ivermectin and non-inactivated vaccine groups, each item showed a statistically significant effect in the non-inactivated vaccine group; the infection rate as of p = 0.023, mortality rate as of p = 0.003, IFR as of p = 0.003, and recovery rate as of p = 0.022. There were no statistical differences between the ivermectin and the inactivated vaccine-approved groups; the infection rate as of p = 0.90, mortality rate as of p = 0.90, infection fatality rate as of p = 0.14, and recovery rate as of p = 0.08.

Vaccine Efficacy Against Ivermectin

Statistical analysis of each vaccine’s efficacy against the ivermectin group was examined by calculating odds ratios and 95% confidence intervals (CIs). The odds ratio and 95% confidence interval (CI) for mortality between the ivermectin and non-inactivated vaccine groups was OR = 1.35 (95% CI, 1.19–1.52, p = 1.4E-06). The efficacy rate of the vaccines against the ivermectin group was 35% (95% CI = 19–52%). The odds ratio and 95% confidence interval (CI) for mortality between ivermectin and the inactivated vaccine-approved groups was OR = 1.18 (95% CI, 1.04–1.34, p = 0.007). The effective rate against the ivermectin group was 18% (95% CI, 4–34%).

Interaction between ivermectin and vaccine by Spearman’s rank correlation coefficient test.

Spearman's rank correlation coefficient test of the interaction between ivermectin and the non-inactivated vaccines (n = 8) showed not significant for all items as of the infection (Rs = -0.48, p = 0.64, mortality (Rs = -0.14, p = 0.64, IFR (Rs = 0.40, p = 0.64) and recovery rates (Rs = -0.40, p = 0.64). The interaction of ivermectin with the inactivated and non-inactivated vaccine combinations (n = 12) was not statistically correlated with infection (Rs = 0.43, p = 0.50), mortality (Rs = 0.33, p = 0.50), IFR (Rs = 0.10, p = 0.50), and recovery rates (Rs = 0.16, p = 0.50).

To make comparisons useful, two issues should be considered. First, is the underlying data of the same type? Second, does it make sense to compare two numbers when the epidemiology and all the other factors involved in the spread of an epidemic are different? That is, the raw epidemiological data obtained should not be used as is but should be adjusted. The three main factors are as follows. (1) Population factors; Population varies realistically from country to country. Demographic factors such as average age and place of residence are particularly important for epidemiological analysis. This could be adjusted according to the average life expectancy of each country. (2) Differences in medical care systems; Do people in the country actively seek treatment, can they easily travel to the hospital, and is excellent treatment paid for? All of these factors vary from place to place. This can be adjusted by the HAQ index. (3) Test systems; While some countries tally the number of people who have been inspected, others record the number of inspections performed, which varies widely. The denominator in calculating the fatality rate is the number of patients with a confirmed diagnosis, but it is highly dependent on the test and medical systems. Since the test was relatively common, albeit imperfectly, in medically developed countries during Delta epidemic, it would be possible to approximate the number of tests based on the average IFR in medically developed countries. The IFR of 0.64 used in this study is almost the same as the estimated IFR of 0.66 by Yang et al [21]. This value is not an estimate for Delta variant, which is twice as infectious, transmissible, and virulent as the conventional strain. Though the average IFR for Delta variant in advanced medical countries in this study is influenced by the vaccines, this value should not affect the comparison as it is used as a criterion for all groups. Although rough, these adjustments appear to have largely eliminated the heterogeneity of the epidemiological data.

Based on the above, epidemiological raw data are adjusted from three points: HAQI, LE, and IFR. In the raw data in Fig. 1, it appears as if ivermectin is more effective against infection than the vaccine groups. However, after adjustment in Fig. 2, the non-inactivated vaccines appear to be superior.

Epidemiological analysis reveals the following; (1) The ivermectin group is inferior to the non-inactivated vaccines in all aspects of infection, mortality, infection fatality, and recovery rates. (2) There is no statistically significant difference in all items between the ivermectin and inactivated vaccine-approved groups. That is, this means that the inactivated vaccine treatment alone is less effective than ivermectin treatment for Delta variant.

However, the ivermectin group is a combination therapy of ivermectin and a vaccine, and the average vaccination rate is 21.2%. For this reason, we must consider the impact of the vaccine in the ivermectin group. 8 of these countries use only the non-inactivated vaccines with an average vaccination rate of 19.6%, and 12 are inactivated vaccine-approved countries that also use the non-inactivated vaccines with an average vaccination rate of 22.2%. These countries have been receiving non-inactivated vaccines from the COVAX facility since March 2021. COVAX provides vaccines for at least 20% of the population of each participating country during 2021. Hence, during the observation period, the inactivated vaccine coverage was lower and the non-inactivated vaccine coverage was higher. Because of this, there appears to be little difference in vaccination rates for both vaccines. From the results of the analysis, the ivermectin group appears to be less effective than the non-inactivated vaccines and superior to the inactivated vaccines. In other words, the values for the ivermectin group can be attributed to the effect of ivermectin alone.

Efficacy of ivermectin against vaccines

The mortality efficacy rate of the non-inactivated vaccines against the ivermectin group is 35% (95% CI = 19–52%). An efficacy rate of 35% means that a person is 35% less likely to become dead than someone who was not vaccinated. The results indicate that ivermectin is effective, although less effective than the non-inactivated vaccines. The mortality effective rate of the inactivated vaccine-approved group against ivermectin is 18% (95% CI, 4–34%). This value shows almost the same effect as the ivermectin group. Thus, ivermectin is more effective than the inactivated vaccines alone.

Interaction between ivermectin and vaccine by Spearman’s rank correlation coefficient test.

The ivermectin group is examined to see if ivermectin therapy has any effect on the vaccine by using Spearman's rank correlation, but there is no significant correlation between them. However, due to the small number of comparisons, the possibility of a negative correlation between the ivermectin and non-inactivated vaccines groups cannot be completely ruled out, given that the correlation coefficient of infection between them is -0.48. The positive correlations coefficient of 0.43 and 0.33 do not completely rule out the possibility that the combination of ivermectin and inactivated vaccines may increase morbidity and mortality. If there is no interaction between non-inactivated and inactivated vaccines, the inactivated vaccines alone would probably have a stronger positive correlation.

These phenomena may be consistent with the situation in Peru and India.

The graphical data from February 2020 to February 2021 of numbers of infection cases and deaths in Peru were obtained from our world in data and Worldometers. This period is not Delta variant epidemic. After the new president, Merino restricted the use of ivermectin and replaced it with the inactivated vaccine on November 17, 2020, the number of infection cases and deaths in Peru skyrocketed to the same level as before. The partial vaccination ratio of 1.0% was done by the inactivated vaccine in February 2021. The prohibition of ivermectin administration may have reduced its vaccine-like effect. The graph shows that the effect of ivermectin lasts for about 5 months, and exhibits a U-shape from August 27, 2020, when the effect is confirmed, to February 2, 2021, when the effect is no longer seen [17, 18]. Since March 2021, the non-inactivated vaccine has been used and the number of infections and deaths has begun to decline. If the interaction between the inactivated vaccine and ivermectin cannot be ignored, even at low doses, it is as if antibody-dependent enhancement (ADE) is occurring. It appears that the only way to acquire ivermectin herd immunity is to perform community-directed treatment of ivermectin (CDTI) or administer it regardless of infection.

In contrast, the exact opposite happened in India. During Delta variant pandemic, ivermectin was approved as a therapeutic agent, and the non-inactivated vaccines were administered in parallel. As of July 2021, the infection was almost under control. Even though the full vaccination rate at this point was about 8%, about 70% had antibodies against SARS-CoV-2 [10, 11, 22]. This means that about 62% of the cases are due to acquired immunity from infection and/or other causes. If all were due to infection, the IFR during Delta variant epidemic in India was 1.36, so 62% infection would result in a mortality rate of 84.3%, which would be out of line with reality. This situation leads us to speculate that ivermectin may have a vaccine effect and that its action may be enhanced when used in combination with vaccines.

In other words, ivermectin originally has a direct chemical effect on SARS-CoV-2. Furthermore, based on the results of this study and the situation in Africa where ivermectin is administered prophylactically, it is presumed that ivermectin has a vaccine action. These findings suggest that ivermectin is not only in chemotherapy against SARS-CoV-2 but also in immunotherapy. Immunotherapy will regulate the host's immunity by fine-tuning the inflammatory signaling cascade to protect it from viruses and restore immune homeostasis.

Ivermectin chemical actions

Ivermectin is originally a broad-spectrum antiparasitic drug, currently approved for the management and treatment of filariasis, scabies, onchocerciasis, and strongyloidiasis, and has antiviral activity against RNA viruses [23]. The chemotherapeutic approach is primarily aimed at disrupting the interaction with the host and/or the virus causing inhibition of its growth and suppressing the inflammatory milieu of the infected patient. In vitro studies in primate cell lines have shown that ivermectin reduces SARS-CoV-2 viral RNA by about 5000-fold within 48 hours [24]. Ivermectin appears to acquire these antiviral properties by binding to the importin-⍺/β complex that the SARS-CoV-2 protein uses to translocate into the host cell nucleus, destabilizing the importin-⍺/β heterodimers [25]. Furthermore, when compared to agents such as Remdesivir and hydroxychloroquine, ivermectin has been found to have a better binding effect on the viral protein targets of SARS-CoV-2 infection, forming a more stable complex, suggesting a more complex role in controlling infection rates [26].

Hypothetical immunological mechanisms of ivermectin

The following hypothetical immunological mechanism of ivermectin is inferred from recent immunological studies on SARS-CoV-2 (Fig. 3).

(1) Hypothetical immune response mechanisms

Docking studies have demonstrated that ivermectin can bind to the SARS-CoV-2 spike receptor-binding domain (RBD) bound to ACE2 [27]. Specifically, ivermectin is demonstrated to have the ability to bind to leucine 91 of the S protein and histidine 378 of the SARS CoV-2-ACE2 receptor complex. The view of the effectiveness of prophylactic administration in Africa suggests that ivermectin may be already bound to the ACE2 receptors. The docking site of ivermectin between the viral spike and the ACE2 receptor would inhibit the attachment of the spike to the human cell membrane [28]. Ivermectin docks in the histidine 378 region of the ACE2 receptor. In a sense, this situation appears as if the cells are in a state of infection. Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. SARS-CoV-2 is classified as a negative-sense RNA virus. Roughly speaking, negative-sense RNA viruses activate the RIG-I-dependent pathway, while positive-sense viruses turn on the melanoma differentiation-associated protein 5 (MDA5) pathway; the caspase activation and recruitment domains (CARDs) of MDA5 and RIG-I interact with the CARD of the adaptor protein mitochondrial antiviral signaling (MAVS) to stimulate signaling [29, 30]. In other words, the ACE2 receptor binding of ivermectin is to put the cells in a pseudo-infectious state from the RNA virus. Upon sensing viral infection, the inactive form of RIG-I undergoes an ATP-dependent conformational change to become the active form, MAVS and the CARD-released active form of RIG-I interacts with the mitochondrially localized via their CARDs [31, 32]. By this pathway, CD8 + and CD4 + T cell responses occur upon negative-sense RNA virus infection. Thus, RIG-I signaling through MAVS is important for determining the quality of the multifunctional T cell response to a negative-sense RNA virus [33–36]. Shortly after pseudo-infection by ivermectin, activated pathogen-specific CD4 + T cells and B cells interact. T cells direct the proliferation of B cells, the switching of antigen receptor (surface-bound Ab) classes, and the establishment of germinal centers (GCs), and some of these B cells differentiate into plasmablasts, an early form of Ab-secreting cells. B cells promote the differentiation of T cells into specialized T follicular helper cells, which then guide the behavior of B cells in the immune response [37]. Also called effector B cells, they produce the first wave of protective antibodies and help eliminate infections.

(2) Autophagy

Autophagy may be involved in the innate immune response against the SARS-CoV-2 pathogen. RIG-I-mediated autophagy is reduced by the loss of MAVS, indicating that the RIG-I pathway signaling axis is important for RIG-I-mediated autophagy. Since the loss of autophagy increases type I interferon responses, induction of autophagy by the RIG-I pathway may also contribute to the prevention of excessive interferon responses as a negative feedback mechanism [38].

These previous immunological and epidemiological reports support that it would be reasonable to assume that ivermectin produces immunity and antibodies against SARS-CoV-2.

Recently, there have been worrisome reports suggesting that antibody-dependent enhancement (ADE), which has been a concern, may be occurring in the late stages after vaccine administration [39]. Since ivermectin may have both chemical and immunological effects on SARS-CoV-2, it is unlikely to cause antibody-dependent enhancement (ADE).

Limitations

Our study has several limitations: (1) This study does not have information about ivermectin alone or the combination of ivermectin with doxycycline or hydroxychloroquine [12,40]. Therefore, it is not possible to assess the true efficacy of ivermectin alone. However, a recent study in Nigeria showed that the use of ivermectin alone in the treatment of patients with SARS-CoV-2 infection was as effective as the triple combination of ivermectin, hydroxychloroquine, and azithromycin in all inflammatory, viral, and respiratory endpoints [41]. (2) The prevalence of Delta variant is from country to country. Therefore, not all countries are prevalent during the 4-month observation period. (3) Because this is an analysis of an inactivated vaccine used in combination with a non-inactivated vaccine rather than an inactivated vaccine alone, the effect of the inactivated vaccine alone is unknown and interactions between vaccines cannot be ruled out. (4) There may be an interaction between ivermectin and the inactivated vaccine that increases morbidity and mortality to SARS-CoV-2, but this cannot be determined. This is because the sole use of inactivated vaccines does not exist outside of China, the country of production.

Ivermectin may have both chemical actions and immune response mechanisms against SARS-CoV-2. And its activity is similar to a vaccine and is more effective than the inactivated vaccines against Delta variant. Ivermectin is less effective but not as pronounced as non-inactivated vaccines. Ivermectin is superior effective than inactivated vaccines. When used in combination with a non-activated vaccine, it may further reduce morbidity. It is supposed that the vaccine effect of ivermectin may last approximately 5 months. A possible immune mechanism is that ivermectin activates the RIG-I pathway to produce innate immunity, antibodies against SARS-CoV-2, and autophagy.

Competing interests: The authors declare no competing interests.

Authors’ contributions: H.T., S.T., and K.K. conceived and designed the study. H.T. and S.T. analyzed the data and wrote the first draft. All authors provided critical revisions. All authors reviewed and approved the final version of the manuscript. H.T., S.T., and K.K. contributed equally to this work.

Data Availability: All data produced in the present work are contained in the manuscript.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

M: Million; R0: Basic Breeding Number, IFR: Infection Fatality Rate, LE: Life Expectancy, HAQI: Healthcare Access and Quality Index, AF: Adjustment Factor, IVM: Ivermectin; RBD: Receptor Binding Domain; RIG-I: Retinoic acid-Induced Gene-I; MAD5: Melanoma differentiation associated protein 5, CARD.I: Melanoma differentiation associated protein 5, CARD.I: Melanoma differentiation associated protein 4, MAD5: Melanoma differentiation associated protein 6 Caspase activation and recruitment domain, MAVS: Mitochondrial antiviral signaling, IRF: Interferon regulatory factor.

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Comparative epidemiology of ivermectin and vaccines against Delta variant based on real-world data and hypothesized mechanisms of ivermectin immunological action

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Abstract

Purpose

Methods

Results

Discussion

Figures

Introduction

Methods

Study design and Data collection

Calculation of adjustment factors to correct medical disparities

Statistical Analysis

Results

Vaccine Efficacy Against Ivermectin

Interaction between ivermectin and vaccine by Spearman’s rank correlation coefficient test.

Discussion

Efficacy of ivermectin against vaccines

Interaction between ivermectin and vaccine by Spearman’s rank correlation coefficient test.

Ivermectin chemical actions

Hypothetical immunological mechanisms of ivermectin

(1) Hypothetical immune response mechanisms

(2) Autophagy

Conclusions

Declarations

Abbreviations

References

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